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Showing 100 Latest Publications
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Olanzapine inhibits the proliferation and induces the differentiation of glioma stem-like cells through modulating the Wnt signaling pathway in vitro.Monday, July 27, 2015
Guo QH, Yang HJ, Wang SD,
European review for medical and pharmacological sciences. Jul-2015
Our results suggest that olanzapine modulates the Wnt signaling pathway through activating the Ca2+ pathway and restraining the β-catenin pathway, leading to the differentiation of GSLCs to ODLCs. It provides exciting prospects that olanzapine might be a new novel chemotherapeutic modality targeting GSLCs for the treatment of glioblastomas.
Mesenchymal stem cells ameliorate LPS-induced acute lung injury through KGF promoting alveolar fluid clearance of alveolar type II cells.Monday, July 27, 2015
Li JW, Wu X,
European review for medical and pharmacological sciences. Jul-2015
AFC was impaired by inflammation insult. MSCs-derived KGF reduced the impaired AFC through up-regulated α1 subunit but not β1 subunit, which might provide a novel therapeutic strategy for ALI.
Current insights into the association of Nestin with tumor angiogenesis.Monday, July 27, 2015
Onisim A, Achimas-Cadariu A, Vlad C, Kubelac P, Achimas-Cadariu P,
Journal of B.U.ON. : official journal of the Balkan Union of Oncology. 28-7-2015
Tumor angiogenesis is regarded as a hallmark of cancer and provides an important target for therapy. Nestin is an intermediate filament protein (IF) originally recognized as a neural stem cell marker. Development and progression of cancer requires sustained angiogenesis, dependent on the proliferation and migration of endothelial cells which seem to be better portrayed by nestin expression in various malignancies such as central nervous system, gastro-intestinal cancers, malignant melanoma, lung, prostate or breast cancer. The purpose of the present review was to emphasize the insights into nestin expression in relation to tumor angiogenesis in different types of cancer. Current evidence suggests that nestin positivity in tumor cells reflects stem-like properties of those cells. Whether or not expressed in both tumor and endothelial cells, nestin overexpression might reflect the extent of angiogenesis and function as a molecular anti-angiogenic target for cancer.
Enhancing eNOS activity with simultaneous inhibition of IKKβ restores vascular function in Ins2(Akita+/-) type-1 diabetic mice.Monday, July 27, 2015
Krishnan M, Janardhanan P, Roman L, Reddick RL, Natarajan M, van Haperen R, Habib SL, de Crom R, Mohan S,
Laboratory investigation; a journal of technical methods and pathology. 27-Jul-2015
The balance of nitric oxide (NO) versus superoxide generation has a major role in the initiation and progression of endothelial dysfunction. Under conditions of high glucose, endothelial nitric oxide synthase (eNOS) functions as a chief source of superoxide rather than NO. In order to improve NO bioavailability within the vessel wall in type-1 diabetes, we investigated treatment strategies that improve eNOS phosphorylation and NO-dependent vasorelaxation. We evaluated methods to increase the eNOS activity by (1) feeding Ins2(Akita) spontaneously diabetic (type-1) mice with l-arginine in the presence of sepiapterin, a precursor of tetrahydrobiopterin; (2) preventing eNOS/NO deregulation by the inclusion of inhibitor kappa B kinase beta (IKKβ) inhibitor, salsalate, in the diet regimen in combination with l-arginine and sepiapterin; and (3) independently increasing eNOS expression to improve eNOS activity and associated NO production through generating Ins2(Akita) diabetic mice that overexpress human eNOS predominantly in vascular endothelial cells. Our results clearly demonstrated that diet supplementation with l-arginine, sepiapterin along with salsalate improved phosphorylation of eNOS and enhanced vasorelaxation of thoracic/abdominal aorta in type-1 diabetic mice. More interestingly, despite the overexpression of eNOS, the in-house generated transgenic eNOS-GFP (TgeNOS-GFP)-Ins2(Akita) cross mice showed an unanticipated effect of reduced eNOS phosphorylation and enhanced superoxide production. Our results demonstrate that enhancement of endogenous eNOS activity by nutritional modulation is more beneficial than increasing the endogenous expression of eNOS by gene therapy modalities.Laboratory Investigation advance online publication, 27 July 2015; doi:10.1038/labinvest.2015.96.
Macrophages mediate cardioprotective cellular postconditioning in acute myocardial infarction.Monday, July 27, 2015
de Couto G, Liu W, Tseliou E, Sun B, Makkar N, Kanazawa H, Arditi M, Marbán E,
The Journal of clinical investigation. 27-Jul-2015
Ischemic injury in the heart induces an inflammatory cascade that both repairs damage and exacerbates scar tissue formation. Cardiosphere-derived cells (CDCs) are a stem-like population that is derived ex vivo from cardiac biopsies; they confer both cardioprotection and regeneration in acute myocardial infarction (MI). While the regenerative effects of CDCs in chronic settings have been studied extensively, little is known about how CDCs confer the cardioprotective process known as cellular postconditioning. Here, we used an in vivo rat model of ischemia/reperfusion (IR) injury-induced MI and in vitro coculture assays to investigate how CDCs protect stressed cardiomyocytes. Compared with control animals, animals that received CDCs 20 minutes after IR had reduced infarct size when measured at 48 hours. CDCs modified the myocardial leukocyte population after ischemic injury. Specifically, introduction of CDCs reduced the number of CD68+ macrophages, and these CDCs secreted factors that polarized macrophages toward a distinctive cardioprotective phenotype that was not M1 or M2. Systemic depletion of macrophages with clodronate abolished CDC-mediated cardioprotection. Using both in vitro coculture assays and a rat model of adoptive transfer after IR, we determined that CDC-conditioned macrophages attenuated cardiomyocyte apoptosis and reduced infarct size, thereby recapitulating the beneficial effects of CDC therapy. Together, our data indicate that CDCs limit acute injury by polarizing an effector macrophage population within the heart.
Monocyte Chemoattractant Protein-Induced Protein 1 (MCPIP1) Enhances Angiogenic and Cardiomyogenic Potential of Murine Bone Marrow-Derived Mesenchymal Stem Cells.Monday, July 27, 2015
Labedz-Maslowska A, Lipert B, Berdecka D, Kedracka-Krok S, Jankowska U, Kamycka E, Sekula M, Madeja Z, Dawn B, Jura J, Zuba-Surma EK,
PloS one. 27-7-2015
The current evidence suggests that beneficial effects of mesenchymal stem cells (MSCs) toward myocardial repair are largely due to paracrine actions of several factors. Although Monocyte chemoattractant protein-induced protein 1 (MCPIP1) is involved in the regulation of inflammatory response, apoptosis and angiogenesis, whether MCPIP1 plays any role in stem cell-induced cardiac repair has never been examined. By employing retroviral (RV)-transduced overexpression of MCPIP1, we investigated the impact of MCPIP1 on viability, apoptosis, proliferation, metabolic activity, proteome, secretome and differentiation capacity of murine bone marrow (BM) - derived MSCs. MCPIP1 overexpression enhanced angiogenic and cardiac differentiation of MSCs compared with controls as indicated by elevated expression of genes accompanying angiogenesis and cardiomyogenesis in vitro. The proangiogenic activity of MCPIP1-overexpressing MSCs (MCPIP1-MSCs) was also confirmed by increased capillary-like structure formation under several culture conditions. This increase in differentiation capacity was associated with decreased proliferation of MCPIP1-MSCs when compared with controls. MCPIP1-MSCs also expressed increased levels of proteins involved in angiogenesis, autophagy, and induction of differentiation, but not adverse inflammatory agents. We conclude that MCPIP1 enhances endothelial and cardiac differentiation of MSCs. Thus, modulating MCPIP1 expression may be a novel approach useful for enhancing the immune-regulatory, anti-apoptotic, anti-inflammatory and regenerative capacity of BM-derived MSCs for myocardial repair and regeneration of ischemic tissues.
Synergistic effect of BMP9 and TGF-β in the proliferation and differentiation of osteoblasts.Monday, July 27, 2015
Li XL, Liu YB, Ma EG, Shen WX, Li H, Zhang YN,
Genetics and molecular research : GMR. 27-7-2015
We investigated the synergistic effect of bone morphoge-netic protein 9 (BMP9) and transforming growth factor (TGF)-b in the transformation of mesenchymal stem cells into osteoblasts. We evalu-ated the effect of BMP9 and TGF-b on the induction of osteoblast for-mation. Mitogen-activated protein kinase (MAPK) pathway-related pro-teins such as p38, extracellular receptor kinase 1/2, and c-Jun N-terminal kinase (JNK) were analyzed. The interactions between TGF-Smad and BMP-MAPK were also studied. BMP9 alone induced the differentiation of mesenchymal stem cells (MSCs) into osteoblasts and enhanced phos-phorylation of p38, extracellular receptor kinase 1/2, and JNK. TGF-b alone failed to induce transformation, but could increase the effect of BMP9. In this process the activation of Smad resulted in activation of the JNK pathway in the MAPK pathway. BMP9 induced osteogenesis of MSC differentiation through the MAKP pathway, while TGF-b contrib-uted to BMP9 enhancement through the Smad-JNK pathway.
Treatment of moyamoya disease by multipoint skull drilling for indirect revascularization combined with mobilization of autologous bone marrow stem cells.Monday, July 27, 2015
Wu R, Su N, Zhang1 And F Jia Z,
Genetics and molecular research : GMR. 13-7-2015
This study discusses the clinical efficacy of multipoint skull drilling for indirect revascularization combined with mobilization of autologous bone marrow stem cells and use of simvastatin in the treatment of moyamoya disease. Seventy-eight patients [control group (group A), 39 patients; experimental group (group B), 39 patients] with moyamoya disease were selected. Group A underwent indirect revas-cularization, and group B, in addition to indirect revascularization, received alternate subcutaneous injections from day 7 post-surgery. The number and differentiation of the mobilized bone marrow stem cells were detected by the proportion of hematopoietic progenitor cell (HPCs) in mononuclear cells (MNCs) in the peripheral blood. There was no statistical difference in the BI (80.2 ± 13.7) and NIHSS (6.7 ± 2.3) scores between the groups before treatment (P > 0.05). The CSS score of group B was 13.5 ± 0.6 and there was a statistical significance compared to group A (18.2 ± 0.8) (P < 0.05). There was no statistical difference in the proportion of CD34+ CDl33+ cells in MNCs in pe-ripheral blood before surgery between the two groups (P > 0.05) and the proportions of CD34+ CDl33+ cells in MNCs in peripheral blood in groups A and B at 30 days after surgery were significantly higher than those before surgery (P < 0.05). Treating moyamoya disease by multipoint skull drilling for indirect revascularization combined with mobilization of autologous bone marrow stem cells and simvastatin is a safe and effective method as it can promote recovery of neurological functions and improve patients' daily living abilities and quality of life.
Accumulation of amino-polyvinyl alcohol-coated superparamagnetic iron oxide nanoparticles in bone marrow: implications for local stromal cells.Monday, July 27, 2015
Schulze F, Gramoun A, Crowe LA, Dienelt A, Akcan T, Hofmann H, Vallée JP, Duda GN, Ode A,
Nanomedicine (London, England). Jul-2015
A-PVA-SPIONs appear suitable for contrast enhancement in bone marrow while our data suggest an influence on the BMSCs biology that necessitates future research.
Pioglitazone for Hepatic Steatosis in HIV/HCV Co-infection.Monday, July 27, 2015
Matthews L, Kleiner D, Chairez C, McManus M, Nettles MJ, Zemanick K, Morse C, Benator D, Kovacs J, Hadigan C,
AIDS research and human retroviruses. 27-Jul-2015
Background Chronic hepatitis C infection frequently coexists with human immunodeficiency virus (HIV) and together are associated with increased hepatic steatosis. Steatosis is a risk factor for progression of liver disease and may persist despite a sustained virologic response to Hepatitis C treatment. Therefore, therapies to target hepatic steatosis are important for individuals with HIV and hepatitis C virus (HCV) co-infection. Methods We completed a 48 week, randomized, double-blind, placebo-controlled trial of pioglitazone (45 mg/d) in 13 subjects with HIV/HCV co-infection. The primary outcome variable was hepatic fat content, measured by magnetic resonance spectroscopy (MRS) imaging. Results Individuals randomized to pioglitazone had a significant decrease in hepatic fat content measured by MRS from baseline (15.1±7.0%) to week 48 (7.6±3.9%), with a mean difference of -7.4% (p=0.02, n=5). There was no significant change in hepatic fat content with placebo. Glycemic control as measured by oral glucose challenge improved significantly with pioglitazone (p=0.047). Though not statistically significant, there were trends towards improved alanine aminotransferase (ALT) and histopathologic grade of steatosis in subjects who received pioglitazone. Pioglitazone was well-tolerated and no one discontinued due to side effects. Conclusions This study demonstrates that 48 weeks of pioglitazone therapy, and not placebo, results in significant reductions in hepatic fat content as measured by MRS in subjects with HIV and HCV co-infection and hepatic steatosis. This small study shows that pioglitazone helps ameliorate steatosis in the context of HIV/HCV co-infection.
Evolving concepts of chondrogenic differentiation: history, state-of-the-art and future perspectives.Monday, July 27, 2015
Tang X, Fan L, Pei M, Zeng L, Ge Z,
European cells & materials. 27-7-2015
As a cell source, multipotent mesenchymal stromal cells or mesenchymal stem cells (MSCs) are promising candidates for chondrogenic differentiation and subsequent cartilage regeneration. From previous literature, it is known that chondrogenic differentiation of MSCs inevitably leads to hypertrophy and subsequent endochondral ossification. In this review, we examine the history of currently established protocols of chondrogenic differentiation and elaborate on the roles of individual components of chondrogenic differentiation medium. We also summarise the effects of physical, chemical and biological factors involved, and propose potential strategies to differentiate MSCs into articular chondrocytes with homogenous mature phenotypes through spatial-temporal incorporation of cell differentiation and chondrogenesis.
β-sarcoglycan gene transfer decreases fibrosis and restores force in LGMD2E mice.Monday, July 27, 2015
Pozsgai ER, Griffin DA, Heller KN, Mendell JR, Rodino-Klapac LR,
Gene therapy. 27-Jul-2015
Limb-girdle muscular dystrophy type 2E (LGMD2E) results from mutations in the β-sarcoglycan (SGCB) gene causing loss of functional protein and concomitant loss of dystrophin-associated proteins. The disease phenotype is characterized by muscle weakness and wasting, and dystrophic features including muscle fiber necrosis, inflammation, and fibrosis. The Sgcb-null mouse recapitulates the clinical phenotype with significant endomysial fibrosis providing a relevant model to test whether gene replacement will be efficacious. We directly addressed this question using a codon optimized human β-sarcoglycan gene (hSGCB) driven by a muscle specific tMCK promoter (scAAVrh74.tMCK.hSGCB). Following isolated limb delivery (5 × 10(11) vg), 91.2% of muscle fibers in the lower limb expressed β-sarcoglycan, restoring assembly of the sarcoglycan complex and protecting the membrane from Evans blue dye leakage. Histological outcomes were significantly improved including decreased central nucleation, normalization of muscle fiber size, decreased macrophages and inflammatory mononuclear cells, and an average of a 43% reduction in collagen deposition in treated muscle compared to untreated muscle at endpoint. These measures correlated with improvement of tetanic force and resistance to eccentric contraction. In 6 month-old mice, as indicated by collagen staining, scAAVrh74.tMCK.hSGCB treatment reduced fibrosis by 42%. This study demonstrates the potential for gene replacement to reverse debilitating fibrosis, typical of muscular dystrophy, thereby providing compelling evidence for movement to clinical gene replacement for LGMD2E.Gene Therapy accepted article preview online, 27 July 2015. doi:10.1038/gt.2015.80.
Microplicae - Specialized Surface Structure of Epithelial Cells of Wet-Surfaced Oral Mucosa.Monday, July 27, 2015
Asikainen P, Sirviö E, Mikkonen JJ, Singh SP, Schulten EA, Ten Bruggenkate CM, Koistinen AP, Kullaa AM,
Ultrastructural pathology. 27-Jul-2015
The surface structure of the superficial cells of the oral mucosa is decorated with numerous membrane ridges, termed microplicae (MPLs). The MPL structure is typical of the epithelial surfaces that are covered with protective mucus. Cell membrane MPLs are no longer seen as passive consequences of cellular activity. The interaction between MPLs and the mucins has been demonstrated, however the role of MPL structure seen on the upper surface of the oral epithelial cells is speculative. The cell surface is of potentially great significance, as it harbors many markers for refined prognosis and targets for oral mucosal diseases and cancer therapy. With these aspects in mind, we conducted the present review of the MPL structure and function in order to form the basis for further studies of MPLs of the oral epithelial cells.
Elastomeric nanocomposite scaffolds made from poly(glycerol sebacate) chemically crosslinked with carbon nanotubes.Monday, July 27, 2015
Gaharwar AK, Patel A, Dolatshahi-Pirouz A, Zhang H, Rangarajan K, Iviglia G, Shin SR, Hussain MA, Khademhosseini A,
Biomaterials science. 2-Jan-2015
Carbon nanotube (CNT)-based nanocomposites often possess properties such as high stiffness, electrical conductivity, and thermal stability and have been studied for various biomedical and biotechnological applications. However, the current design approaches utilize CNTs as physical fillers, and thus, the true potential of CNT-based nanocomposites has not been realized. Here, we introduce a general approach to fabricating stiff, elastomeric nanocomposites from poly(glycerol sebacate) (PGS) and CNTs. The covalent crosslinking between the nanotubes and polymer chains resulted in novel property combinations that are not observed in conventional nanocomposites. The addition of 1% CNTs resulted in a five-fold increase in the tensile modulus and a six-fold increase in compression modulus compared with PGS alone, which is far superior to the previously reported studies for CNT-based nanocomposites. Despite a significant increase in mechanical stiffness, the elasticity of the network was not compromised and the resulting nanocomposites showed more than 94% recovery. This study demonstrates that the chemical conjugation of CNTs to a PGS backbone results in stiff and elastomeric nanocomposites. Additionally, in vitro studies using human mesenchymal stem cells (hMSCs) indicated that the incorporation of CNTs into the PGS network significantly enhanced the differentiation potential of the seeded hMSCs, rendering them potentially suitable for applications ranging from scaffolding in musculoskeletal tissue engineering to biosensors in biomedical devices.
NF-κB activation impairs somatic cell reprogramming in ageing.Monday, July 27, 2015
Soria-Valles C, Osorio FG, Gutiérrez-Fernández A, De Los Angeles A, Bueno C, Menéndez P, Martín-Subero JI, Daley GQ, Freije JM, López-Otín C,
Nature cell biology. 27-Jul-2015
Ageing constitutes a critical impediment to somatic cell reprogramming. We have explored the regulatory mechanisms that constitute age-associated barriers, through derivation of induced pluripotent stem cells (iPSCs) from individuals with premature or physiological ageing. We demonstrate that NF-κB activation blocks the generation of iPSCs in ageing. We also show that NF-κB repression occurs during cell reprogramming towards a pluripotent state. Conversely, ageing-associated NF-κB hyperactivation impairs the generation of iPSCs by eliciting the reprogramming repressor DOT1L, which reinforces senescence signals and downregulates pluripotency genes. Genetic and pharmacological NF-κB inhibitory strategies significantly increase the reprogramming efficiency of fibroblasts from Néstor-Guillermo progeria syndrome and Hutchinson-Gilford progeria syndrome patients, as well as from normal aged donors. Finally, we demonstrate that DOT1L inhibition in vivo extends lifespan and ameliorates the accelerated ageing phenotype of progeroid mice, supporting the interest of studying age-associated molecular impairments to identify targets of rejuvenation strategies.
Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells.Monday, July 27, 2015
Patsch C, Challet-Meylan L, Thoma EC, Urich E, Heckel T, O'Sullivan JF, Grainger SJ, Kapp FG, Sun L, Christensen K, Xia Y, Florido MH, He W, Pan W, Prummer M, Warren CR, Jakob-Roetne R, Certa U, Jagasia R, Freskgård PO, Adatto I, Kling D, Huang P, Zon LI, Chaikof EL, Gerszten RE, Graf M, Iacone R, Cowan CA,
Nature cell biology. 27-Jul-2015
The use of human pluripotent stem cells for in vitro disease modelling and clinical applications requires protocols that convert these cells into relevant adult cell types. Here, we report the rapid and efficient differentiation of human pluripotent stem cells into vascular endothelial and smooth muscle cells. We found that GSK3 inhibition and BMP4 treatment rapidly committed pluripotent cells to a mesodermal fate and subsequent exposure to VEGF-A or PDGF-BB resulted in the differentiation of either endothelial or vascular smooth muscle cells, respectively. Both protocols produced mature cells with efficiencies exceeding 80% within six days. On purification to 99% via surface markers, endothelial cells maintained their identity, as assessed by marker gene expression, and showed relevant in vitro and in vivo functionality. Global transcriptional and metabolomic analyses confirmed that the cells closely resembled their in vivo counterparts. Our results suggest that these cells could be used to faithfully model human disease.
A microfluidic device for epigenomic profiling using 100 cells.Monday, July 27, 2015
Cao Z, Chen C, He B, Tan K, Lu C,
Nature methods. 27-Jul-2015
The sensitivity of chromatin immunoprecipitation (ChIP) assays poses a major obstacle for epigenomic studies of low-abundance cells. Here we present a microfluidics-based ChIP-seq protocol using as few as 100 cells via drastically improved collection of high-quality ChIP-enriched DNA. Using this technology, we uncovered many new enhancers and super enhancers in hematopoietic stem and progenitor cells from mouse fetal liver, suggesting that enhancer activity is highly dynamic during early hematopoiesis.
Peptide Bioink: Self-Assembling Nanofibrous Scaffolds for 3D Organotypic Cultures.Monday, July 27, 2015
Hauser CA, Loo Y, Lakshmanan A, Ni M, Toh LL, Wang S,
Nano letters. 27-Jul-2015
Printable scaffolds with adequate mechanical strength and stiffness are sought after to ensure viability of printed cells and tissues. We report the first peptide bioinks - lysine-containing hexapeptides which self-assemble into stable, nanofibrous three-dimensional hydrogels with unprecedented stiffness of up to 40kPa. These biocompatible scaffolds support the 3D culture of human stem cells and differentiation of primary cells into organotypic (gastrointestinal and skin) structures for high-throughput screening, diagnosis and tissue engineering.
The forkhead transcription factor Fox01 is regulated by both a stimulatory thyrotropin receptor antibody and insulin-like growth factor-1 in orbital fibroblasts from patients with Graves' ophthalmopathy.Monday, July 27, 2015
Kumar S, Coenen MJ, Iyer S, Bahn RS,
Thyroid : official journal of the American Thyroid Association. 27-Jul-2015
These data point to FoxO1 as an important mediator of TSAb and IGF-1 action via their cognate receptors in GO orbital fibroblasts. These findings provide a link between the low FoxO1 protein levels demonstrated in GO orbital tissue and the tissue remodeling characteristic of GO, and suggest novel therapy for GO aimed at increasing nuclear expression of FoxO1 in GO target cells.
miR-204 regulated the proliferation of dairy goat spermatogonial stem cells via targeting to Sirt1.Monday, July 27, 2015
Hua J,
Rejuvenation research. 27-Jul-2015
The regulation of SSCs proliferation and self-renewal was a complex process. Several studies on microRNA regulation the mammalian spermatogenesis have been reported. Here, we predicted the miRNAs targeting SIRT1 and Dual luciferase experiment confirmed that miR-204 was interacted with Sirt1-3'UTR. The expression of miR-204 and Sirt1 in dairy goat testicles were investigated and the results showed that the expression pattern of Sirt1 was similar to miR-204 in the temporal-spatial distribution. The overexpression of Sirt1 in goat SSCs can promoted SSCs' self-renewal genes expression and cell proliferation. Furthermore, miRNA sequencing results showed that Sirt1 had a higher expression level in dairy goat CD49f+ and CD90+ SSCs, but miR-204 was opposite. In vitro assay, Sirt1 was significantly down-regulated in dairy goat SSCs when transfected with miR-204 mimics, this indicated that Sirt1 was a target of miR-204 in dairy goat. Based on the results of RT-qPCR, FACS and Western Blot, we found that the overexpression of Sirt1 in goat SSCs can promote the cells proliferation and change the self-renewal and pluripotency gene expression, and miR-204 was involved in the regulation of dairy goat SSCs prolifetation via Sirt1.
Österreichische Gesellschaft für Dermatologie und Venerologie (ÖGDV).Monday, July 27, 2015
Saxinger W,
Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. Aug-2015
An Acid-Triggered Degradable and Fluorescent Nanoscale Drug Delivery System with Enhanced Cytotoxicity to Cancer Cells.Monday, July 27, 2015
An J, Dai X, Wu Z, Zhao Y, Lu Z, Guo Q, Zhang X, Li C,
Biomacromolecules. 27-Jul-2015
To reduce side-effects of anticancer drugs, development of nanocarriers with precise biological functions is a critical requirement. In this study, the multifunctional nanoparticles combining imaging and therapy for tumor-targeted delivery of hydrophobic anticancer drugs were prepared via self-assembly of amphiphilic copolymers obtained using RAFT polymerization, specifically, acid-labile ortho ester and galactose. First, boron-dipyrromethene dye-conjugated chain transfer agent provides fluorescent imaging capability for diagnostic application. Second, nanoparticles were stable under physiological conditions but degraded in acidic tumor microenvironment, leading to enhanced anticancer efficacy. Third, the application of biocompatible glycopolymers efficiently increased the target-to-background ratio through carbohydrate-protein interactions. Data from cell viability, cellular internalization, flow cytometry, biodistribution and anticancer efficacy tests showed that the drug-loaded nanoparticles were capable of inhibiting cancer cell proliferation with significantly enhanced capacity. Our newly developed multifunctional nanoparticles may thus facilitate the development of effective drug delivery systems for application in diagnosis and therapy of cancer.
A mechanistic overview of dendritic cell-mediated HIV-1 trans infection: the story so far.Monday, July 27, 2015
Kijewski SD, Gummuluru S,
Future virology. Mar-2015
Despite progress in antiretroviral therapy, HIV-1 rebound after cessation of antiretroviral therapy suggests that establishment of long-term cellular reservoirs of virus is a significant barrier to functional cure. There is considerable evidence that dendritic cells (DCs) play an important role in systemic virus dissemination. Although productive infection of DCs is inefficient, DCs capture HIV-1 and transfer-captured particles to CD4(+) T cells, a mechanism of DC-mediated HIV-1 trans infection. Recent findings suggest that DC-mediated trans infection of HIV-1 is dependent on recognition of GM3, a virus-particle-associated host-derived ligand, by CD169 expressed on DCs. In this review, we describe mechanisms of DC-mediated HIV-1 trans infection and discuss specifically the role of CD169 in establishing infection in CD4(+) T cells.
Haploidentical hematopoietic stem cell transplantation in children and adolescents with acquired severe aplastic anemia.Monday, July 27, 2015
Im HJ, Koh KN, Seo JJ,
Korean journal of pediatrics. Jun-2015
Severe aplastic anemia (SAA) is a life-threatening disorder for which allogeneic hematopoietic stem cell transplantation (HSCT) is the current available curative treatment. HSCT from matched sibling donors (MSDs) is the preferred therapy for children with acquired SAA. For patients who lack MSDs, immunosuppressive therapy (IST) is widely accepted as a first-line treatment before considering HCT from an unrelated donor (URD). Given the recent progress in HSCT using URDs for childhood SAA, well-matched URDs became a realistic alternative for pediatric patients who have no suitable related donors and who are refractory to IST. However, it is quite challenging to treat patients with refractory SAA who lack suitable related or URDs. Even though haploidentical HSCT from genetically mismatched family members seemed to be an attractive procedure with the amazing benefit of readily available donors for most patients, early attempts were disappointing because of refractory graft-versus-host disease (GVHD) and excessively high transplant-related mortality. Recent advances with effective ex vivo depletion of T cells or unmanipulated in vivo regulation of T cells, better supportive care, and optimal conditioning regimens have significantly improved the outcome of haploidentical transplant. Besides considerable progress in the treatment of malignant diseases, recent emerging evidences for haploidentical HSCT in SAA has provided additional therapeutic options for patients with refractory diseases. Further improvements to decrease the rates of graft failure, GVHD, and infectious complications will facilitate the emergence of haploidentical HSCT as a front-line therapy for treating acquired SAA in children and adolescents who have no suitably matched donors.
Analytical strategies for studying stem cell metabolism.Monday, July 27, 2015
Arnold JM, Choi WT, Sreekumar A, Maletić-Savatić M,
Frontiers in biology. Apr-2015
Owing to their capacity for self-renewal and pluripotency, stem cells possess untold potential for revolutionizing the field of regenerative medicine through the development of novel therapeutic strategies for treating cancer, diabetes, cardiovascular and neurodegenerative diseases. Central to developing these strategies is improving our understanding of biological mechanisms responsible for governing stem cell fate and self-renewal. Increasing attention is being given to the significance of metabolism, through the production of energy and generation of small molecules, as a critical regulator of stem cell functioning. Rapid advances in the field of metabolomics now allow for in-depth profiling of stem cells both in vitro and in vivo, providing a systems perspective on key metabolic and molecular pathways which influence stem cell biology. Understanding the analytical platforms and techniques that are currently used to study stem cell metabolomics, as well as how new insights can be derived from this knowledge, will accelerate new research in the field and improve future efforts to expand our understanding of the interplay between metabolism and stem cell biology.
Delivery of iPS-NPCs to the Stroke Cavity within a Hyaluronic Acid Matrix Promotes the Differentiation of Transplanted Cells.Monday, July 27, 2015
Lam J, Lowry WE, Carmichael ST, Segura T,
Advanced functional materials. 26-Nov-2014
Stroke is the leading cause of adult disability with ~80% being ischemic. Stem cell transplantation has been shown to improve functional recovery. However, the overall survival and differentiation of these cells is still low. The infarct cavity is an ideal location for transplantation as it is directly adjacent to the highly plastic peri-infarct region. Direct transplantation of cells near the infarct cavity has resulted in low cell viability. Here we deliver neural progenitor cells derived from induce pluripotent stem cells (iPS-NPC) to the infarct cavity of stroked mice encapsulated in a hyaluronic acid hydrogel matrix to protect the cells. To improve the overall viability of transplanted cells, each step of the transplantation process was optimized. Hydrogel mechanics and cell injection parameters were investigated to determine their effects on the inflammatory response of the brain and cell viability, respectively. Using parameters that balanced the desire to keep surgery invasiveness minimal and cell viability high, iPS-NPCs were transplanted to the stroke cavity of mice encapsulated in buffer or the hydrogel. While the hydrogel did not promote stem cell survival one week post-transplantation, it did promote differentiation of the neural progenitor cells to neuroblasts.
Overexpression of MALT1-A20-NF-κB in adult B-cell acute lymphoblastic leukemia.Monday, July 27, 2015
Xu Y, Hu J, Wang X, Xuan L, Lai J, Xu L, Chen S, Yang L, Luo G, Zhu K, Wu X, Li Y,
Cancer cell international. 2015
We found that MALT1-A20-NF-κB is overexpressed in adult B-ALL, which may be related to the pathogenesis of B-ALL, and this pathway may be considered a potentially attractive target for the development of B-ALL therapeutics.
Cross-Generational Reproductive Fitness Enforced by Microchimeric Maternal Cells.Monday, July 27, 2015
Kinder JM, Jiang TT, Ertelt JM, Xin L, Strong BS, Shaaban AF, Way SS,
Cell. 22-Jul-2015
Exposure to maternal tissue during in utero development imprints tolerance to immunologically foreign non-inherited maternal antigens (NIMA) that persists into adulthood. The biological advantage of this tolerance, conserved across mammalian species, remains unclear. Here, we show maternal cells that establish microchimerism in female offspring during development promote systemic accumulation of immune suppressive regulatory T cells (Tregs) with NIMA specificity. NIMA-specific Tregs expand during pregnancies sired by males expressing alloantigens with overlapping NIMA specificity, thereby averting fetal wastage triggered by prenatal infection and non-infectious disruptions of fetal tolerance. Therefore, exposure to NIMA selectively enhances reproductive success in second-generation females carrying embryos with overlapping paternally inherited antigens. These findings demonstrate that genetic fitness, canonically thought to be restricted to Mendelian inheritance, is enhanced in female placental mammals through vertically transferred maternal cells that promote conservation of NIMA and enforce cross-generational reproductive benefits.
The Tissue Inhibitor of Metalloproteinases-1 Increases the Clonogenic Efficiency of Human Hematopoietic Progenitor Cells Through CD63/PI3K/AKT Signaling.Monday, July 27, 2015
Rossi L, Forte D, Migliardi G, Salvestrini V, Buzzi M, Ricciardi MR, Licchetta R, Tafuri A, Bicciato S, Cavo M, Catani L, Lemoli RM, Curti A,
Experimental hematology. 23-Jul-2015
Initially described as an endogenous inhibitor of proteases, the Tissue Inhibitor of MetalloProteinases-1 (TIMP-1) also displays cytokine-like functions. TIMP-1 is a soluble protein, whose levels are increased under inflammatory conditions. We recently found that TIMP-1(-/-) mice have decreased bone marrow (BM) cellularity and the engraftment capability of TIMP-1(-/-) HSCs is impaired, due to proliferation defects. Here, we investigated the role of rhTIMP-1 in human hematopoietic stem/progenitor cells (HSPCs) and elucidated the downstream pathway ignited by rhTIMP-1. We found that rhTIMP-1 affects in vitro cell survival, proliferation and, particularly, clonogenic expansion of CD34(+) HSPCs, without compromising their short-term engraftment potential after transplantation into immunodeficient mice. These effects are independent on matrix metalloproteinase (MMP)-inhibition and rely on TIMP-1's binding to the tetraspanin membrane receptor CD63. Further investigation indicated that rhTIMP-1 stimulation induces PI3K recruitment and AKT phosphorylation, both presiding over survival/proliferation pathways in HSPCs. Downstream targets of pAKT are also modulated, including the proliferation marker CycD1, which levels are increased upon exposure to rhTIMP-1. These findings indicate that rhTIMP-1 promotes clonogenic expansion and survival in human progenitors via the activation of the CD63/PI3K/pAKT signaling pathway, suggesting that TIMP-1 might be a key player in the network of pro-inflammatory factors modulating HSPC functions.
Identification of osteoblast stimulating factor-5 as a negative regulator in B lymphopoietic niche.Monday, July 27, 2015
Fujita N, Ichii M, Maeda T, Saitoh N, Yokota T, Yamawaki K, Kakitani M, Tomizuka K, Oritani K, Kanakura Y,
Experimental hematology. 23-Jul-2015
Recent studies have revealed the crucial role of niche which supports B lymphocyte differentiation from hematopoietic stem cells. In this study, we aimed to identify a novel regulator of B lymphopoiesis secreted in the specific niche using signal sequence trap method. Among the identified proteins from MS5 stromal cells, expression of pleiotrophin, placental proliferin-2 and osteoblast stimulating factor-5 (OSF-5) was dominantly high in several stromal cell lines. We found that OSF-5 suppressed the early B lymphopoiesis in transgenic mice producing the target protein. The number of pre B and immature B cells was reduced more than half of control in the transgenic mice. In vitro studies showed that secreted variant of OSF-5 inhibited the proliferation and colony formation of pre B cells, while cell-intrinsic form had no influence on B lymphopoiesis. The main components of B lymphopoietic niche, osteoblasts in mice and mesenchymal cells in human are main producers of OSF-5. These results define a novel mechanism of B lymphopoiesis in BM. In the specific niche, B lymphocyte differentiation is fine-tuned by negative regulators as well as supportive factors.
Mesenchymal Stem Cells Respond to Hypoxia by Increasing Diacylglycerols.Monday, July 27, 2015
Lakatos K, Kalomoiris S, Merkely B, Nolta JA, Fierro FA,
Journal of cellular biochemistry. 24-Jul-2015
Mesenchymal stem cells (MSC) are currently being tested clinically for a plethora of conditions, with most approaches relying on the secretion of paracrine signals by MSC to modulate the immune system, promote wound healing and induce angiogenesis. Hypoxia has been shown to affect MSC proliferation, differentiation, survival and secretory profile. Here, we investigate changes in the lipid composition of human bone marrow-derived MSC after exposure to hypoxia. Using mass spectrometry, we compared the lipid profiles of MSC derived from five different donors, cultured for two days in either normoxia (control) or hypoxia (1% oxygen). Hypoxia induced a significant increase of total triglycerides, fatty acids and diacylglycerols (DG). Remarkably, reduction of DG levels using the phosphatidylcholine-specific phospholipase C inhibitor D609 inhibited the secretion of VEGF and Angiopoietin-2, but increased the secretion of interleukin-8, without affecting significantly their respective mRNA levels. Functionally, incubation of MSC in hypoxia with D609 inhibited the potential of the cells to promote migration of human endothelial cells in a wound/scratch assay. Hence, we show that hypoxia induces in MSC an increase of DG that may affect the angiogenic potential of these cells. This article is protected by copyright. All rights reserved.
Prediction of drug-induced nephrotoxicity and injury mechanisms with human induced pluripotent stem cell-derived cells and machine learning methods.Monday, July 27, 2015
Kandasamy K, Chuah JK, Su R, Huang P, Eng KG, Xiong S, Li Y, Chia CS, Loo LH, Zink D,
Scientific reports. 2015
The renal proximal tubule is a main target for drug-induced toxicity. The prediction of proximal tubular toxicity during drug development remains difficult. Any in vitro methods based on induced pluripotent stem cell-derived renal cells had not been developed, so far. Here, we developed a rapid 1-step protocol for the differentiation of human induced pluripotent stem cells (hiPSC) into proximal tubular-like cells. These proximal tubular-like cells had a purity of >90% after 8 days of differentiation and could be directly applied for compound screening. The nephrotoxicity prediction performance of the cells was determined by evaluating their responses to 30 compounds. The results were automatically determined using a machine learning algorithm called random forest. In this way, proximal tubular toxicity in humans could be predicted with 99.8% training accuracy and 87.0% test accuracy. Further, we studied the underlying mechanisms of injury and drug-induced cellular pathways in these hiPSC-derived renal cells, and the results were in agreement with human and animal data. Our methods will enable the development of personalized or disease-specific hiPSC-based renal in vitro models for compound screening and nephrotoxicity prediction.
High-dose therapy improves the bone remodelling compartment canopy coverage and bone formation in multiple myeloma.Monday, July 27, 2015
Hinge M, Delaisse JM, Plesner T, Clasen-Linde E, Salomo M, Andersen TL,
British journal of haematology. 27-Jul-2015
Bone loss in multiple myeloma (MM) is caused by an uncoupling of bone formation to resorption trigged by malignant plasma cells. Increasing evidence indicates that the bone remodelling compartment (BRC) canopy, which normally covers the remodelling sites, is important for coupled bone remodelling. Loss of this canopy has been associated with bone loss. This study addresses whether the bone remodelling in MM is improved by high-dose therapy. Bone marrow biopsies obtained from 20 MM patients, before and after first-line treatment with high-dose melphalan followed by autologous stem cell transplantation, and from 20 control patients with monoclonal gammopathy of undetermined significance were histomorphometrically investigated. This investigation confirmed that MM patients exhibited uncoupled bone formation to resorption and reduced canopy coverage. More importantly, this study revealed that a good response to anti-myeloma treatment increased the extent of formative bone surfaces with canopy, and reduced the extent of eroded surfaces without canopy, reverting the uncoupled bone remodelling, while improving canopy coverage. The association between improved coupling and the canopy coverage supports the notion that canopies are critical for the coupling of bone formation to resorption. Furthermore, this study supports the observation that systemic bone disease in MM can be reversed in MM patients responding to anti-myeloma treatment.
Boundary Caps Give Rise to Neurogenic Stem Cells and Terminal Glia in the Skin.Monday, July 27, 2015
Gresset A, Coulpier F, Gerschenfeld G, Jourdon A, Matesic G, Richard L, Vallat JM, Charnay P, Topilko P,
Stem cell reports. 22-Jul-2015
While neurogenic stem cells have been identified in rodent and human skin, their manipulation and further characterization are hampered by a lack of specific markers. Here, we perform genetic tracing of the progeny of boundary cap (BC) cells, a neural-crest-derived cell population localized at peripheral nerve entry/exit points. We show that BC derivatives migrate along peripheral nerves to reach the skin, where they give rise to terminal glia associated with dermal nerve endings. Dermal BC derivatives also include cells that self-renew in sphere culture and have broad in vitro differentiation potential. Upon transplantation into adult mouse dorsal root ganglia, skin BC derivatives efficiently differentiate into various types of mature sensory neurons. Together, this work establishes the embryonic origin, pathway of migration, and in vivo neurogenic potential of a major component of skin stem-like cells. It provides genetic tools to study and manipulate this population of high interest for medical applications.
MicroRNA-153 Regulates the Acquisition of Gliogenic Competence by Neural Stem Cells.Monday, July 27, 2015
Tsuyama J, Bunt J, Richards LJ, Iwanari H, Mochizuki Y, Hamakubo T, Shimazaki T, Okano H,
Stem cell reports. 22-Jul-2015
Mammalian neural stem/progenitor cells (NSPCs) sequentially generate neurons and glia during CNS development. Here we identified miRNA-153 (miR-153) as a modulator of the temporal regulation of NSPC differentiation. Overexpression (OE) of miR-153 delayed the onset of astrogliogenesis and maintained NSPCs in an undifferentiated state in vitro and in the developing cortex. The transcription factors nuclear factor I (NFI) A and B, essential regulators of the initiation of gliogenesis, were found to be targets of miR-153. Inhibition of miR-153 in early neurogenic NSPCs induced precocious gliogenesis, whereas NFIA/B overexpression rescued the anti-gliogenic phenotypes induced by miR-153 OE. Our results indicate that miR-mediated fine control of NFIA/B expression is important in the molecular networks that regulate the acquisition of gliogenic competence by NSPCs in the developing CNS.
Wound-healing potential of human umbilical cord blood-derived mesenchymal stromal cells in vitro-a pilot study.Monday, July 27, 2015
You HJ, Namgoong S, Han SK, Jeong SH, Dhong ES, Kim WK,
Cytotherapy. 23-Jul-2015
Human UCB-MSCs may have greater capacity for diabetic wound healing than allogeneic or autologous fibroblasts, especially in angiogenesis.
Comparison of autologous versus allogeneic epithelial-like stem cell treatment in an in vivo equine skin wound model.Monday, July 27, 2015
Broeckx SY, Borena BM, Van Hecke L, Chiers K, Maes S, Guest DJ, Meyer E, Duchateau L, Martens A, Spaas JH,
Cytotherapy. 23-Jul-2015
These results confirm the first hypothesis and partially support the second hypothesis. Besides macroscopic improvements, both autologous and allogeneic EpSCs had similar effects on granulation tissue formation, vascularization and early cellular immune response.
Investigation on Single-walled Carbon Nanotubes-Liposomes Conjugate to Treatment Tumor with Dual-mechanism.Monday, July 27, 2015
Zhu X, Huang H, Zhang Y, Xie Y, Hou L, Zhang H, Zhang Z,
Current pharmaceutical biotechnology. 27-Jul-2015
Single-walled carbon nanotubes (SWNT) have been widely explored as carriers for drug delivery because of their large surface area, high near-infrared absorption coefficient and facile transport through cellular membranes. In this study, Lysine (Lys) modified SWNT-liposomes conjugate loaded with doxorubicin (DOX) was designed to enhance the targeted drug delivery and antitumor effect. The conjugate (DOX-Lys/SWNT-Lip) was prepared with pH gradient methods, and the mean particle size and drug entrapment efficiency were 223±5.9 nm and 85.9 %, respectively. In vitro drug release study showed that DOX released much slowly from DOX-Lys/SWNT-Lip than from DOX solution, but faster than that of DOX-Lys/SWNT. DOX-Lys/SWNT-Lip could efficiently cross the cell membrane and afford higher anti-tumor efficacy on MCF-7 cells in vitro. For in vivo experiment, normal saline (N.S.), and DOX or DOX-Lys/SWNTLip were given to the S180 tumor bearing mice by i.v. administration, and followed by exposing the tumor site to nearinfrared laser (NIR) irradiation at 808 nm for 2 min. The relative tumor volumes in DOX-Lys/SWNT-Lip group and DOX group were obviously smaller than those of N.S. group. When combined with NIR laser irradiation, the suppression on tumor growth was much stronger. In conclusion, this study may provide potentially viable clinical strategies for tumor treatment with chemotherapy and photothermal therapy dual-mechanism.
miR-218 is essential to establish motor neuron fate as a downstream effector of Isl1-Lhx3.Monday, July 27, 2015
Thiebes KP, Nam H, Cambronne XA, Shen R, Glasgow SM, Cho HH, Kwon JS, Goodman RH, Lee JW, Lee S, Lee SK,
Nature communications. 2015
While microRNAs have emerged as an important component of gene regulatory networks, it remains unclear how microRNAs collaborate with transcription factors in the gene networks that determines neuronal cell fate. Here we show that in the developing spinal cord, the expression of miR-218 is directly upregulated by the Isl1-Lhx3 complex, which drives motor neuron fate. Inhibition of miR-218 suppresses the generation of motor neurons in both chick neural tube and mouse embryonic stem cells, suggesting that miR-218 plays a crucial role in motor neuron differentiation. Results from unbiased RISC-trap screens, in vivo reporter assays and overexpression studies indicated that miR-218 directly represses transcripts that promote developmental programs for interneurons. In addition, we found that miR-218 activity is required for Isl1-Lhx3 to effectively induce motor neurons and suppress interneuron fates. Together our results reveal an essential role of miR-218 as a downstream effector of the Isl1-Lhx3 complex in establishing motor neuron identity.
Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction.Monday, July 27, 2015
Labbadia J, Morimoto RI,
Molecular cell. 22-Jul-2015
The heat shock response (HSR) is essential for proteostasis and cellular health. In metazoans, aging is associated with a decline in quality control, thus increasing the risk for protein conformational disease. Here, we show that in C. elegans, the HSR declines precipitously over a 4 hr period in early adulthood coincident with the onset of reproductive maturity. Repression of the HSR occurs due to an increase in H3K27me3 marks at stress gene loci, the timing of which is determined by reduced expression of the H3K27 demethylase jmjd-3.1. This results in a repressed chromatin state that interferes with HSF-1 binding and suppresses transcription initiation in response to stress. The removal of germline stem cells preserves jmjd-3.1 expression, suppresses the accumulation of H3K27me3 at stress gene loci, and maintains the HSR. These findings suggest that competing requirements of the germline and soma dictate organismal stress resistance as animals begin reproduction.
Fanconi Anemia Mesenchymal Stromal Cells-Derived Glycerophospholipids Skew Hematopoietic Stem Cell Differentiation Through Toll-Like Receptor Signaling.Monday, July 27, 2015
Amarachintha S, Sertorio M, Wilson A, Li X, Pang Q,
Stem cells (Dayton, Ohio). 24-Jul-2015
Fanconi anemia (FA) patients develop bone marrow (BM) failure or leukemia. One standard care for these devastating complications is hematopoietic stem cell transplantation. We identified a group of mesenchymal stromal cells (MSCs)-derived metabolites, glycerophospholipids, and their endogenous inhibitor, 5-(tetradecyloxy)-2-furoic acid (TOFA), as regulators of donor hematopoietic stem and progenitor cells. We provided two pieces of evidence that TOFA could improve hematopoiesis-supporting function of FA MSCs: (a) limiting-dilution cobblestone area-forming cell assay revealed that TOFA significantly increased cobblestone colonies in Fanca-/- or Fancd2-/- cocultures compared to untreated cocultures. (b) Competitive repopulating assay using output cells collected from cocultures showed that TOFA greatly alleviated the abnormal expansion of the donor myeloid (CD45.2+Gr1+Mac1+) compartment in both peripheral blood and BM of recipient mice transplanted with cells from Fanca-/- or Fancd2-/- cocultures. Furthermore, mechanistic studies identified Tlr4 signaling as the responsible pathway mediating the effect of glycerophospholipids. Thus, targeting glycerophospholipid biosynthesis in FA MSCs could be a therapeutic strategy to improve hematopoiesis and stem cell transplantation. Stem Cells 2015.
Distribution of intestinal stem cell markers in colorectal precancerous lesions.Monday, July 27, 2015
Jang BG, Kim HS, Kim KJ, Rhee YY, Kim WH, Kang GH,
Histopathology. 25-Jul-2015
The expression and distribution profile of ISC markers possibly provides insights into the organization of stem and progenitor-like cells in each type of precancerous lesion of CRC. This article is protected by copyright. All rights reserved.
Versatility of stem and progenitor cells and the instructive actions of cytokines on hematopoiesis.Monday, July 27, 2015
Brown G, Mooney CJ, Alberti-Servera L, Muenchow LV, Toellner KM, Ceredig R, Rolink A,
Critical reviews in clinical laboratory sciences. 27-Jul-2015
For many years, developing hematopoietic cells have been strictly compartmentalized into a rare population of multi-potent self-renewing hematopoietic stem cells (HSC), multi-potent hematopoietic progenitor cells (MPP) that are undergoing commitment to particular lineage fates, and recognizable precursor cells that mature towards functional blood and immune cells. A single route to each end-cell type is prescribed in the "classical" model for the architecture of hematopoiesis. Recent findings have led to the viewpoint that HSCs and MPPs are more versatile than previously thought. Underlying this are multiple routes to a particular fate and cells having clandestine fate options even when they have progressed some way along a pathway. The primary role of cytokines during hematopoiesis has long been seen to be regulation of the survival and proliferation of developing hematopoietic cells. Some cytokines now clearly have instructive actions on cell-fate decisions. All this leads to a new way of viewing hematopoiesis whereby versatile HSC and MPP are directed towards lineage outcomes via cytokine regulated cell-fate decisions. This means greater flexibility to the shaping of hematopoiesis.
Hydrogels for Therapeutic Cardiovascular Angiogenesis.Monday, July 27, 2015
Rufaihah AJ, Seliktar D,
Advanced drug delivery reviews. 23-Jul-2015
Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. While growth factor or cell therapy are promising, the retention of bioactive agents in the highly vascularized myocardium is limited and prevents sustained activation needed for adequate cellular responses. Various types of biomaterials with different physical and chemical properties have been developed to improve the localized delivery of growth factor and/or cells for therapeutic angiogenesis in ischemic tissues. Hydrogels are particularly advantageous as carrier systems because they are structurally similar to the tissue extracellular matrix (ECM), they can be processed under relatively mild conditions and can be delivered in a minimally invasive manner. Moreover, hydrogels can be designed to degrade in a timely fashion that coincides with the angiogenic process. For these reasons, hydrogels have shown great potential as pro-angiogenic matrices. This paper reviews a few of the hydrogel systems currently being applied together with growth factor delivery and/or cell therapy to promote therapeutic angiogenesis in ischemic tissues, with emphasis on myocardial applications.
Cell Competition Modifies Adult Stem Cell and Tissue Population Dynamics in a JAK-STAT-Dependent Manner.Monday, July 27, 2015
Kolahgar G, Suijkerbuijk SJ, Kucinski I, Poirier EZ, Mansour S, Simons BD, Piddini E,
Developmental cell. 22-Jul-2015
Throughout their lifetime, cells may suffer insults that reduce their fitness and disrupt their function, and it is unclear how these potentially harmful cells are managed in adult tissues. We address this question using the adult Drosophila posterior midgut as a model of homeostatic tissue and ribosomal Minute mutations to reduce fitness in groups of cells. We take a quantitative approach combining lineage tracing and biophysical modeling and address how cell competition affects stem cell and tissue population dynamics. We show that healthy cells induce clonal extinction in weak tissues, targeting both stem and differentiated cells for elimination. We also find that competition induces stem cell proliferation and self-renewal in healthy tissue, promoting selective advantage and tissue colonization. Finally, we show that winner cell proliferation is fueled by the JAK-STAT ligand Unpaired-3, produced by Minute(-/+) cells in response to chronic JNK stress signaling.
RAD18 Is a Maternal Limiting Factor Silencing the UV-Dependent DNA Damage Checkpoint in Xenopus Embryos.Monday, July 27, 2015
Kermi C, Prieto S, van der Laan S, Tsanov N, Recolin B, Uro-Coste E, Delisle MB, Maiorano D,
Developmental cell. 22-Jul-2015
In early embryos, the DNA damage checkpoint is silent until the midblastula transition (MBT) because of maternal limiting factors of unknown identity. Here we identify the RAD18 ubiquitin ligase as one such factor in Xenopus. We show, in vitro and in vivo, that inactivation of RAD18 function leads to DNA damage-dependent checkpoint activation, monitored by CHK1 phosphorylation. Moreover, we show that the abundance of both RAD18 and PCNA monoubiquitylated (mUb) are developmentally regulated. Increased DNA abundance limits the availability of RAD18 close to the MBT, thereby reducing PCNA(mUb) and inducing checkpoint derepression. Furthermore, we show that this embryonic-like regulation can be reactivated in somatic mammalian cells by ectopic RAD18 expression, therefore conferring resistance to DNA damage. Finally, we find high RAD18 expression in cancer stem cells highly resistant to DNA damage. Together, these data propose RAD18 as a critical embryonic checkpoint-inhibiting factor and suggest that RAD18 deregulation may have unexpected oncogenic potential.
Laser-scanning cytometry can quantify human adipocyte browning and proves effectiveness of irisin.Monday, July 27, 2015
Kristóf E, Doan-Xuan QM, Bai P, Bacso Z, Fésüs L,
Scientific reports. 2015
Laser-scanning cytometry is presented as a tool allowing population scale analysis of ex vivo human brown adipogenic differentiation. It combines texture analysis and detection of Ucp1 protein content in single brown adipocytes of mixed cell populations with gene expression pattern and functional characteristics of browning. Using this method we could validate mouse data in human samples demonstrating the effectiveness of irisin to induce "beige" differentiation of subcutaneous white adipocytes.
Tetraspanin 3 Is Required for the Development and Propagation of Acute Myelogenous Leukemia.Monday, July 27, 2015
Kwon HY, Bajaj J, Ito T, Blevins A, Konuma T, Weeks J, Lytle NK, Koechlein CS, Rizzieri D, Chuah C, Oehler VG, Sasik R, Hardiman G, Reya T,
Cell stem cell. 22-Jul-2015
Acute Myelogenous Leukemia (AML) is an aggressive cancer that strikes both adults and children and is frequently resistant to therapy. Thus, identifying signals needed for AML propagation is a critical step toward developing new approaches for treating this disease. Here, we show that Tetraspanin 3 is a target of the RNA binding protein Musashi 2, which plays a key role in AML. We generated Tspan3 knockout mice that were born without overt defects. However, Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in mouse models of AML. Additionally, Tspan3 inhibition blocked growth of AML patient samples, suggesting that Tspan3 is also important in human disease. As part of the mechanism, we show that Tspan3 deficiency disabled responses to CXCL12/SDF-1 and led to defects in AML localization within the niche. These identify Tspan3 as an important regulator of aggressive leukemias and highlight a role for Tspan3 in oncogenesis.
Functional Correction of Large Factor VIII Gene Chromosomal Inversions in Hemophilia A Patient-Derived iPSCs Using CRISPR-Cas9.Monday, July 27, 2015
Park CY, Kim DH, Son JS, Sung JJ, Lee J, Bae S, Kim JH, Kim DW, Kim JS,
Cell stem cell. 22-Jul-2015
Hemophilia A is an X-linked genetic disorder caused by mutations in the F8 gene, which encodes the blood coagulation factor VIII. Almost half of all severe hemophilia A cases result from two gross (140-kbp or 600-kbp) chromosomal inversions that involve introns 1 and 22 of the F8 gene, respectively. We derived induced pluripotent stem cells (iPSCs) from patients with these inversion genotypes and used CRISPR-Cas9 nucleases to revert these chromosomal segments back to the WT situation. We isolated inversion-corrected iPSCs with frequencies of up to 6.7% without detectable off-target mutations based on whole-genome sequencing or targeted deep sequencing. Endothelial cells differentiated from corrected iPSCs expressed the F8 gene and functionally rescued factor VIII deficiency in an otherwise lethal mouse model of hemophilia. Our results therefore provide a proof of principle for functional correction of large chromosomal rearrangements in patient-derived iPSCs and suggest potential therapeutic applications.
p53 activity contributes to defective interfollicular epidermal differentiation, in hyperproliferative murine skin.Monday, July 27, 2015
Cottle DL, Kretzschmar K, Gollnick HP, Quist SR,
The British journal of dermatology. 25-Jul-2015
We conclude aberrant non-apoptotic p53 activity contributes, in-part, to abnormal differentiation and granular layer defects. This article is protected by copyright. All rights reserved.
Epigenetic silencing of GDF1 disrupts SMAD signaling to reinforce gastric cancer development.Monday, July 27, 2015
Yang W, Mok MT, Li MS, Kang W, Wang H, Chan AW, Chou JL, Chen J, Ng EK, To KF, Yu J, Chan MW, Chan FK, Sung JJ, Cheng AS,
Oncogene. 27-Jul-2015
Accumulating evidence reveals the effectiveness of epigenetic therapy in gastric cancer. However, the molecular mechanisms and targets underlying such therapeutic responses remain elusive. Herein, we report an aberrant yet therapeutically rectifiable epigenetic signaling in gastric carcinogenesis. Administration of DNA-demethylating drug 5-aza-2'-deoxycytidine (5-aza-dC) reduced gastric cancer incidence by ~74% (P<0.05) in N-nitroso-N-methylurea-treated mice. Through genome-wide methylation scanning, novel promoter hypermethylation-silenced and drug-targeted genes were identified in the resected murine stomach tumors and tissues. We uncovered that growth/differentiation factor 1 (Gdf1), a member of the transforming growth factor-β superfamily, was silenced by promoter hypermethylation in control tumor-bearing mice, but became reactivated in 5-aza-dC-treated mice (P<0.05). In parallel, the downregulated SMAD2/3 phosphorylation in gastric cancer was revived by 5-aza-dC in vivo. Such hypermethylation-dependent silencing and 5-aza-dC-mediated reactivation of GDF1-SMAD2/3 activity was conserved in human gastric cancer cells (P<0.05). Subsequent functional characterization further revealed the antiproliferative activity of GDF1, which was exerted through activation of SMAD2/3/4-mediated signaling, transcriptional controls on p15, p21 and c-Myc cell-cycle regulators and phosphorylation of retinoblastoma protein. Clinically, hypermethylation and loss of GDF1 was significantly associated with reduced phosphorylated-SMAD2/3 and poor survival in stomach cancer patients (P<0.05). Taken together, we demonstrated a causal relationship between DNA methylation and a tumor-suppressive pathway in gastric cancer. Epigenetic silencing of GDF1 abrogates the growth-inhibitory SMAD signaling and renders proliferation advantage to gastric epithelial cells during carcinogenesis. This study lends support to epigenetic therapy for gastric cancer chemoprevention and identifies a potential biomarker for prognosis.Oncogene advance online publication, 27 July 2015; doi:10.1038/onc.2015.276.
Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer.Monday, July 27, 2015
Timsah Z, Ahmed Z, Ivan C, Berrout J, Gagea M, Zhou Y, Pena GN, Hu X, Vallien C, Kingsley CV, Lu Y, Hancock JF, Liu J, Gladden AB, Mills GB, Lopez-Berestein G, Hung MC, Sood AK, Bogdanov M, Ladbury JE,
Oncogene. 27-Jul-2015
In the absence of extracellular stimulation the adaptor protein growth factor receptor-bound protein (Grb2) and the phospholipase Plcγ1 compete for the same binding site on fibroblast growth factor receptor 2 (FGFR2). Reducing cellular Grb2 results in upregulation of Plcγ1 and depletion of the phospholipid PI(4,5)P2. The functional consequences of this event on signaling pathways are unknown. We show that the decrease in PI(4,5)P2 level under non-stimulated conditions inhibits PTEN activity leading to the aberrant activation of the oncoprotein Akt. This results in excessive cell proliferation and tumor progression in a xenograft mouse model. As well as defining a novel mechanism of Akt phosphorylation with important therapeutic consequences, we also demonstrate that differential expression levels of FGFR2, Plcγ1 and Grb2 correlate with patient survival. Oncogenesis through fluctuation in the expression levels of these proteins negates extracellular stimulation or mutation and defines them as novel prognostic markers in ovarian cancer.Oncogene advance online publication, 27 July 2015; doi:10.1038/onc.2015.279.
CXCR7 mediates TGFβ1-promoted EMT and tumor-initiating features in lung cancer.Monday, July 27, 2015
Wu YC, Tang SJ, Sun GH, Sun KH,
Oncogene. 27-Jul-2015
In the tumor microenvironment, chemokine system has a critical role in tumorigenesis and metastasis. The acquisition of stem-like properties by cancer cells is involved in metastasis and drug resistance, which are pivotal problems that result in poor outcomes in patients with lung cancer. Patients with advanced lung cancer present high plasma levels of transforming growth factor-β1 (TGFβ1), which correlate with poor prognostic features. Therefore, TGFβ1 may be important in the tumor microenvironment, where chemokines are widely expressed. However, the role of chemokines in TGFβ1-induced tumor progression still remains unclear. In our study, TGFβ1 upregulated CXC chemokine receptor expression, migration, invasion, epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation in lung adenocarcinoma. We found that CXCR7 was the most upregulated chemokine receptor induced by TGFβ1. CXCR7 knockdown resulted in reduction of migration, invasion and EMT induced by TGFβ1, whereas CXCR4 knockdown did not reverse TGFβ1-promoted EMT. CXCR7 silencing significantly decreased cancer sphere-forming capacity, stem-like properties, chemoresistance and TGFβ1-induced CSC tumor initiation in vivo. In clinical samples, high TGFβ1 and CXCR7 expression was significantly associated with the late stages of lung adenocarcinoma. Moreover, TGFβ1 and CXCR7 coexpression was positively correlated with the CSC marker, CD44, which is associated with lymph node metastasis. Besides, patients with high expression of both CXCR7 and TGFβ1 presented a significantly worse survival rate. These results suggest that the TGFβ1-CXCR7 axis may be a prognostic marker and may provide novel targets for combinational therapies to be used in the treatment of advanced lung cancer in the future.Oncogene advance online publication, 27 July 2015; doi:10.1038/onc.2015.274.
Results of a multicenter phase II trial of brentuximab vedotin as second-line therapy before autologous transplantation in relapsed/refractory Hodgkin Lymphoma.Monday, July 27, 2015
Chen R, Palmer JM, Martin P, Tsai N, Kim Y, Chen BT, Popplewell L, Siddiqi T, Thomas SH, Mott M, Sahebi F, Armenian S, Leonard J, Nademanee A, Forman SJ,
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 23-Jul-2015
This multicenter prospective phase II study examines the activity and tolerability of brentuximab vedotin as second-line therapy in patients with Hodgkin lymphoma that was relapsed or refractory after induction therapy. Brentuximab vedotin (1.8 mg/kg) was administered intravenously on day 1 of a 21-day cycle for a total of 4 cycles. Patients then proceeded to autologous hematopoietic cell transplantation (AHCT), if eligible, with or without additional salvage therapy, based on remission status post brentuximab vedotin. The primary endpoint was overall response rate (ORR). Secondary endpoints were safety, stem cell mobilization/collection, AHCT outcomes and association of CD68+ with outcomes. Of 37 patients, the ORR was 68% (13 complete remission, 12 partial remission). The regimen was well tolerated with few grade 3/4 adverse events including lymphopenia (1), neutropenia (3), rash (2), and hyperuricemia (1). Thirty-three (89%) patients were able to proceed to AHCT, with 24 (65%) in CR at time of AHCT. Thirteen patients in CR, 4 in PR and 1 in SD (49%) received AHCT without salvage combination chemotherapy. CD 68 expression did not correlate with response to brentuximab vedotin. The median number of stem cells mobilized was 6.0 x 10(6) (2.6-34) and median number of days to obtain minimum collection (2 x 10(6)) was 2 (1-6). Brentuximab vedotin as second-line therapy is active, well tolerated, and allows adequate stem cell collection and engraftment. For Hodgkin lymphoma patients with relapsed/refractory disease post-induction therapy, second-line brentuximab vedotin, followed by combination chemotherapy for residual disease, can effectively bridge patients to AHCT.
The immune response of bovine mammary epithelial cells to live or heat-inactivated Mycoplasma bovis.Monday, July 27, 2015
Zbinden C, Pilo P, Frey J, Bruckmaier RM, Wellnitz O,
Veterinary microbiology. 9-Jul-2015
Mycoplasma bovis is an emerging bacterial agent causing bovine mastitis. Although these cell wall-free bacteria lack classical virulence factors, they are able to activate the immune system of the host. However, effects on the bovine mammary immune system are not yet well characterized and detailed knowledge would improve the prevention and therapy of mycoplasmal mastitis. The aim of this study was to investigate the immunogenic effects of M. bovis on the mammary gland in an established primary bovine mammary epithelial cell (bMEC) culture system. Primary bMEC of four different cows were challenged with live and heat-inactivated M. bovis strain JF4278 isolated from acute bovine mastitis, as well as with the type strain PG45. The immune response was evaluated 6 and 24h after mycoplasmal challenge by measuring the relative mRNA expression of selected immune factors by quantitative PCR. M. bovis triggered an immune response in bMEC, reflected by the upregulation of tumor necrosis factor-α, interleukin(IL)-1β, IL-6, IL-8, lactoferrin, Toll-like receptor-2, RANTES, and serum amyloid A mRNA. Interestingly, this cellular reaction was only observed in response to live, but not to heat-inactivated M. bovis, in contrast to other bacterial pathogens of mastitis such as Staphylococcus aureus. This study provides evidence that bMEC exhibit a strong inflammatory reaction in response to live M. bovis. The lack of a cellular response to heat-inactivated M. bovis supports the current hypothesis that mycoplasmas activate the immune system through secreted secondary metabolites.
piggyBac-ing models and new therapeutic strategies.Monday, July 27, 2015
Woodard LE, Wilson MH,
Trends in biotechnology. 23-Jul-2015
DNA transposons offer an efficient nonviral method of permanently modifying the genomes of mammalian cells. The piggyBac transposon system has proven effective in genomic engineering of mammalian cells for preclinical applications, including gene discovery, simultaneous multiplexed genome modification, animal transgenesis, gene transfer in vivo achieving long-term gene expression in animals, and the genetic modification of clinically relevant cell types, such as induced pluripotent stem cells and human T lymphocytes. piggyBac has many desirable features, including seamless excision of transposons from the genomic DNA and the potential to target integration events to desired DNA sequences. In this review, we explore these recent applications and also highlight the unique advantages of using piggyBac for developing new molecular therapeutic strategies.
Metabolic suppression during mesodermal differentiation of embryonic stem cells identified by single-cell comprehensive gene expression analysis.Monday, July 27, 2015
Zhou Y, Fujisawa I, Ino K, Matsue T, Shiku H,
Molecular bioSystems. 27-Jul-2015
Flk-1 (VEGF receptor 2) is a well-defined mesodermal progenitor marker and the Flk-1-positive (Flk-1(+)) cells derived from embryonic stem cells (ESCs) have been known to generate hemangioblasts and cardiovascular progenitor cells, which are formed in the early and late stages of differentiation, respectively. In this study, we separated Flk-1(+) and Flk-1(-) cells from spontaneously differentiating embryoid bodies (EBs) of mouse ESCs. We found that cell aggregates derived from late stage Flk-1(+) cells had a relatively small size and a low oxygen consumption rate (OCR) compared with those derived from Flk-1(-) cells. Furthermore, using single-cell comprehensive gene expression analysis, we found that both Flk-1(+) and Flk-1(-) cells could be categorized into subgroups with either low or high glucose metabolic activity. We observed that metabolic suppression occurs in cells expressing an intermediate level of both Nanog and Pou5f1. Taken together, our data suggested that the temporary metabolic suppression is an intrinsic feature of mesodermal differentiation.
Tim-3 and Tim-4 as the potential targets for antitumor therapy.Monday, July 27, 2015
Cheng L, Ruan Z,
Human vaccines & immunotherapeutics. 25-Jul-2015
Abstracts Both Tim-3 and Tim-4 belong to the T-cell immunoglobulin and mucin domain (Tim) gene family, which plays a critical role in immunoregulation. Tim-3 has been suggested as a negative regulator of anti-tumor immunity due to its function on inducing T cells exhaustion in cancer. In addition to its expression on exhausted T cells, Tim-3 also has been reported to up-regulate on nature killer (NK) cells and promote NK cells functionally exhausted in cancer. While Tim-3 selectively expression on most types of leukemia stem cells, it promotes the progression of acute myeloid leukemia. Recently, data from experimental models of tumor discovered that Tim-3 and Tim-4 up-regulation on tumor associated dendritic cells and macrophages attenuated the anti-tumor effects of cancer vaccines and chemotherapy. Moreover, co-blockage of Tim-3 and PD-1, Tim-3 and CD137, Tim-3 and carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) could enhance cell-mediated immunity in advanced tumor, and combined treatment with anti-Tim-3 and anti-Tim-4 mAbs further increase the efficacy of cancer vaccines. The therapeutic manipulation of TIM-3 and TIM-4 may provide a novel strategy to improve the clinical efficacy of cancer immunotherapy.
Embryonic stem cell-derived pancreatic endoderm transplant with MCT1-suppressing miR-495 attenuates type II diabetes in mice.Monday, July 27, 2015
Liang D, Zhang Y, Han J, Wang W, Liu Y, Li J, Jiang X,
Endocrine journal. 25-Jul-2015
Type 2 diabetes mellitus (T2D) is a chronic metabolic disorder resulting from defects in both insulin secretion and insulin activity. The deficit and dysfunction of insulin secreting β-cells are signature symptoms of T2D. Additionally, in pancreatic β-cells, a small group of genes that are abundantly expressed in most other tissues is highly selectively repressed. Monocarboxylate transporter 1 (MCT1) is one of these genes. In this study, we identified an MCT1-suppressing microRNA (hsa-miR-495) and used this microRNA together with human embryonic stem cell (hESC) derived pancreatic endoderm (PE) cells transplanted into a high-fat diet induced T2D mouse model. Glucose metabolism significantly improved and other symptoms of T2D were attenuated after the procedure. Our findings support the potential for T2D treatment using the combination of microRNA and hESC differentiated PE cells.
Intravenous Preload of Mesenchymal Stem Cells Rescues Erectile Function in a Rat Model of Cavernous Nerve Injury.Monday, July 27, 2015
Takayanagi A, Sasaki M, Kataoka-Sasaki Y, Kobayashi K, Matsuda Y, Oka S, Masumori N, Kocsis JD, Honmou O,
The journal of sexual medicine. 24-Jul-2015
Intravenous preload of MSCs before a CN injury may prevent or reduce experimental ED. Takayanagi A, Sasaki M, Kataoka-Sasaki Y, Kobayashi K, Matsuda Y, Oka S, Masumori N, Kocsis JD and Honmou O. Intravenous preload of mesenchymal stem cells rescues erectile function in a rat model of cavernous nerve injury. J Sex Med **;**:**-**.
A detailed quantitative outcome measure of glycosaminoglycans in human articular cartilage for cell therapy and tissue engineering strategies.Monday, July 27, 2015
Kuiper NJ, Sharma A,
Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 23-Jul-2015
As an outcome measure, FACE offers the potential of a complete, detailed assessment of all GAGs and offers more information that the widely used 1,9-dimethylmethylene blue (DMMB) dye assay. FACE could be very useful in the evolving cartilage regeneration field.
β-Arrestin scaffolds and signaling elements essential for the obestatin/GPR39 system that determine the myogenic program in human myoblast cells.Monday, July 27, 2015
Santos-Zas I, Gurriarán-Rodríguez U, Cid-Díaz T, Figueroa G, González-Sánchez J, Bouzo-Lorenzo M, Mosteiro CS, Señarís J, Casanueva FF, Casabiell X, Gallego R, Pazos Y, Mouly V, Camiña JP,
Cellular and molecular life sciences : CMLS. 27-Jul-2015
Obestatin/GPR39 signaling stimulates skeletal muscle repair by inducing the expansion of satellite stem cells as well as myofiber hypertrophy. Here, we describe that the obestatin/GPR39 system acts as autocrine/paracrine factor on human myogenesis. Obestatin regulated multiple steps of myogenesis: myoblast proliferation, cell cycle exit, differentiation and recruitment to fuse and form multinucleated hypertrophic myotubes. Obestatin-induced mitogenic action was mediated by ERK1/2 and JunD activity, being orchestrated by a G-dependent mechanism. At a later stage of myogenesis, scaffolding proteins β-arrestin 1 and 2 were essential for the activation of cell cycle exit and differentiation through the transactivation of the epidermal growth factor receptor (EGFR). Upon obestatin stimulus, β-arrestins are recruited to the membrane, where they functionally interact with GPR39 leading to Src activation and signalplex formation to EGFR transactivation by matrix metalloproteinases. This signalplex regulated the mitotic arrest by p21 and p57 expression and the mid- to late stages of differentiation through JNK/c-Jun, CAMKII, Akt and p38 pathways. This finding not only provides the first functional activity for β-arrestins in myogenesis but also identify potential targets for therapeutic approaches by triggering specific signaling arms of the GPR39 signaling involved in myogenesis.
Targeting non-receptor tyrosine kinases using small molecule inhibitors: an overview of recent advances.Monday, July 27, 2015
Hojjat-Farsangi M,
Journal of drug targeting. 27-Jul-2015
Protein tyrosine kinases are enzymes that catalyze the transfer of phosphate groups from ATP to tyrosine residues on other proteins as substrate. Phosphorylation at tyrosine residues regulates several functions, including enzyme activity, cellular localization, signal transduction and interactions between proteins. Non-receptor tyrosine kinases (nRTKs) are one of the main players in intracellular signaling pathways. Dysregulation of nRTKs leads to their constitutive activation, which might contribute to initiation or progression of cancer. Therefore, targeting dysregulated nRTKs may prevent the process of tumorigenesis. Targeted-based cancer therapy (TBCT) methods and agents or personalized medicine have emerged as the main tools for cancer treatment. Currently, several TBCT agents, including monoclonal antibodies (mAbs) and small molecules inhibitors of tyrosine kinases (TKIs) have been developed. TKIs of cytoplasmic kinases inhibit intracellular signaling pathways and interfere with tumor cell functions. In this article, the recent progresses in development of TKIs of nRTKs approved by the US Food and Drug Administration (FDA) and current promising TKIs in pre-clinical and clinical settings have been reviewed.
[Research Progress in Seeding Cells of Peripheral Nerve].Monday, July 27, 2015
Shi G, Hu Y,
Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi. Apr-2015
Seeding cells play an important role in the peripheral nerve damage repair. Seeding cells studied conse- quently in peripheral nerve are Schwann cells, bone marrow mesenchymal stem cells and neural stem cells. Schwann cells, the first seeding cells, are various unique glial cells in the peripheral nervous system, which can form the myelin sheath for insulation and package of the neuron projecting axons in the peripheral nervous system so that the conduction velocity of the nerve signal was accelerated. It can be proved that Schwann cells played an important role in the maintenance of peripheral nerve function and in the regeneration process after peripheral nerve injury. The second, bone marrow mesenchymal stem cells are the various mesenchymal stem cells mainly exist in the systemic connective tissues and organs. These functional stem cells are often studied at present, and it has been found that they have exuberant proliferation and differentiation potentials. Neural stem cells, mentioned the third in sequence, are the kind of pluripotent cells with multi-directional differentiation, which could conduct the self-renewal function, and generate and differentiate neurons, astrocytes and oligodendrocytes through asymmetric cell division. These three types of seed cells are discussed in this paper.
[In vitro study of TGF-β1-induced epithelial-mesenchymal transition of keloid epithelial cells].Monday, July 27, 2015
Yan L, Cao R, Pan B, Wang L, Lyu X, Sun X, Xiao R,
Zhonghua zheng xing wai ke za zhi = Zhonghua zhengxing waike zazhi = Chinese journal of plastic surgery. Mar-2015
TGF-β1, initiated EMT in keloid epithelial cells by inducing the up-regulation of snail2, and TGF-β1,/Smad3 signaling pathway was involved in EMT. EMT could change the phenotype of epithelial stem cells in keloid.
Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase.Sunday, July 26, 2015
Oh YS, Kim SH, Cho GW,
Cellular and molecular neurobiology. 26-Jul-2015
Alteration of DNA methylation is highly associated with aging and neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). Remedying these aberrant methylation patterns may serve to improve these diseases. Previously, we reported that human bone marrow mesenchymal stromal cells isolated from ALS patients (ALS-MSCs) have functionally decreased stem cell potency, and excessively express DNA methyltransferases (DNMTs). In this study, we examined the correlation between excessive DNMT expression and functional decline in ALS-MSCs. The DNMT inhibitor RG108 was used for this. RG108-treated ALS-MSCs exhibit increased expression of the anti-senescence genes TERT, VEGF, and ANG, and decreased expression of the senescence-related genes ATM and p21. The activity of SA-β-galactosidase and the expression of senescence proteins p53 and p16 were reduced in RG108-treated ALS-MSCs. The abilities of cell migration and protection against oxidative damage were improved in the treated ALS-MSCs. In neuronal differentiation experiments, the treated MSCs more effectively differentiated into neuron-like cells. These results suggest that ALS-MSC function can be restored by inhibiting excessively expressed DNMTs, an approach that may ultimately provide better efficacy in stem cell therapy.
Novel Small Molecule Inhibitors of Cancer Stem Cell Signaling Pathways.Sunday, July 26, 2015
Abetov D, Mustapova Z, Saliev T, Bulanin D, Batyrbekov K, Gilman CP,
Stem cell reviews. 26-Jul-2015
The main aim of oncologists worldwide is to understand and then intervene in the primary tumor initiation and propagation mechanisms. This is essential to allow targeted elimination of cancer cells without altering normal mitotic cells. Currently, there are two main rival theories describing the process of tumorigenesis. According to the Stochastic Model, potentially any cell, once defunct, is capable of initiating carcinogenesis. Alternatively the Cancer Stem Cell (CSC) Model posits that only a small fraction of undifferentiated tumor cells are capable of triggering carcinogenesis. Like healthy stem cells, CSCs are also characterized by a capacity for self-renewal and the ability to generate differentiated progeny, possibly mediating treatment resistance, thus leading to tumor recurrence and metastasis. Moreover, molecular signaling profiles are similar between CSCs and normal stem cells, including Wnt, Notch and Hedgehog pathways. Therefore, development of novel chemotherapeutic agents and proteins (e.g., enzymes and antibodies) specifically targeting CSCs are attractive pharmaceutical candidates. This article describes small molecule inhibitors of stem cell pathways Wnt, Notch and Hedgehog, and their recent chemotherapy clinical trials.
The Role of Hypoxia and Cancer Stem Cells in Renal Cell Carcinoma Pathogenesis.Sunday, July 26, 2015
Myszczyszyn A, Czarnecka AM, Matak D, Szymanski L, Lian F, Kornakiewicz A, Bartnik E, Kukwa W, Kieda C, Szczylik C,
Stem cell reviews. 26-Jul-2015
The cancer stem cell (CSC) model has recently been approached also in renal cell carcinoma (RCC). A few populations of putative renal tumor-initiating cells (TICs) were identified, but they are indifferently understood; however, the first and most thoroughly investigated are CD105-positive CSCs. The article presents a detailed comparison of all renal CSC-like populations identified by now as well as their presumable origin. Hypoxic activation of hypoxia-inducible factors (HIFs) contributes to tumor aggressiveness by multiple molecular pathways, including the governance of immature stem cell-like phenotype and related epithelial-to-mesenchymal transition (EMT)/de-differentiation, and, as a result, poor prognosis. Due to intrinsic von Hippel-Lindau protein (pVHL) loss of function, clear-cell RCC (ccRCC) develops unique pathological intra-cellular pseudo-hypoxic phenotype with a constant HIF activation, regardless of oxygen level. Despite satisfactory evidence concerning pseudo-hypoxia importance in RCC biology, its influence on putative renal CSC-like largely remains unknown. Thus, the article discusses a current knowledge of HIF-1α/2α signaling pathways in the promotion of undifferentiated tumor phenotype in general, including some experimental findings specific for pseudo-hypoxic ccRCC, mostly dependent from HIF-2α oncogenic functions. Existing gaps in understanding both putative renal CSCs and their potential connection with hypoxia need to be filled in order to propose breakthrough strategies for RCC treatment.
Nuclear Mechanics and Stem Cell Differentiation.Sunday, July 26, 2015
Mao X, Gavara N, Song G,
Stem cell reviews. 26-Jul-2015
Stem cells are characterized by their self-renewal and multi-lineage differentiation potential. Stem cell differentiation is a prerequisite for the application of stem cells in regenerative medicine and clinical therapy. In addition to chemical stimulation, mechanical cues play a significant role in regulating stem cell differentiation. The integrity of mechanical sensors is necessary for the ability of cells to respond to mechanical signals. The nucleus, the largest and stiffest cellular organelle, interacts with the cytoskeleton as a key mediator of cell mechanics. Nuclear mechanics are involved in the complicated interactions of lamins, chromatin and nucleoskeleton-related proteins. Thus, stem cell differentiation is intimately associated with nuclear mechanics due to its indispensable role in mechanotransduction and mechanical response. This paper reviews several main contributions of nuclear mechanics, highlights the hallmarks of the nuclear mechanics of stem cells, and provides insight into the relationship between nuclear mechanics and stem cell differentiation, which may guide clinical applications in the future.
Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer's disease.Sunday, July 26, 2015
Mita T, Furukawa-Hibi Y, Takeuchi H, Hattori H, Yamada K, Hibi H, Ueda M, Yamamoto A,
Behavioural brain research. 22-Jul-2015
Alzheimer's disease (AD) is a progressive, neurodegenerative disease characterized by a decline in cognitive abilities and the appearance of β-amyloid plaques in the brain. Although the pathogenic mechanisms associated with AD are not fully understood, activated microglia releasing various neurotoxic factors, including pro-inflammatory cytokines and oxidative stress mediators, appear to play major roles. Here, we investigated the therapeutic benefits of a serum-free conditioned medium (CM) derived from the stem cells of human exfoliated deciduous teeth (SHEDs) in a mouse model of AD. The intranasal administration of SHEDs in these mice resulted in substantially improved cognitive function. SHED-CM contained factors involved in multiple neuroregenerative mechanisms, such as neuroprotection, axonal elongation, neurotransmission, the suppression of inflammation, and microglial regulation. Notably, SHED-CM attenuated the pro-inflammatory responses induced by β-amyloid plaques, and generated an anti-inflammatory/tissue-regenerating environment, which was accompanied by the induction of anti-inflammatory M2-like microglia. Our data suggest that SHED-CM may provide significant therapeutic benefits for AD.
Human adipose-derived mesenchymal stem cells attenuate collagen antibody-induced autoimmune arthritis by inducing expression of FCGIIB receptors.Monday, July 27, 2015
Yi H, Kang KY, Kim Y, Jung H, Rim YA, Park N, Kim J, Jung SM, Park SH, Ju JH,
BMC musculoskeletal disorders. 2015
This is a study to show that ASCs have anti-arthritic effects in CAIA mice. Modulation of FCGRs by ASCs might be a therapeutic mechanism in this antibody-associated arthritis model.
Intrinsic facilitation of adult peripheral nerve regeneration by the Sonic hedgehog morphogen.Sunday, July 26, 2015
Martinez JA, Kobayashi M, Krishnan A, Webber C, Christie K, Guo G, Singh V, Zochodne DW,
Experimental neurology. 22-Jul-2015
Intrinsic molecular determinants of neurodevelopmental outcomes assume new, albeit related roles during adult neural regeneration. Here we studied and identified a facilitatory role for Sonic hedgehog protein (Shh), a morphogen that influences motor neuron floor plate architecture, during adult peripheral neuron regeneration. Shh and its receptors were expressed in adult dorsal root ganglia (DRG) neurons, axons and glia and trended toward higher levels following axotomy injury. Knockdown of Shh in adult sensory neurons resulted in decreased outgrowth and branching in vitro, identifying a role for Shh in facilitating outgrowth. The findings argued for an intrinsic action to support neuron regeneration. Support of advancement and turning however, were not identified in adult sensory neuron growth cones in response to local extrinsic gradients of Shh. That intrinsic Shh supported the regrowth of peripheral nerves after injury was confirmed by the analysis of axon regrowth from the proximal stumps of transected sciatic nerves. By exposing regenerating axons to local infusions of Shh siRNA in vivo within a conduit bridging the transected proximal and distal stumps, we achieved local knockdown of Shh. In response, there was attenuated axonal and Schwann cell outgrowth beyond the transection zone. Unlike its role during neurodevelopment, Shh facilitates but does not confer regenerative outgrowth properties to adult neurons alone. Exploring the differing properties of morphogens and related proteins in the adult nervous system identifies new and important roles for them.
Mitochondrial Biology: From Molecules to Disease Symposium.Sunday, July 26, 2015
Kabekkodu SP, Chakrabarty S, Shukla V, Varghese VK, Singh KK, Thangaraj K, Satyamoorthy K,
Mitochondrion. 22-Jul-2015
As an integral part of the cell, mitochondria play a pivotal role in the regulation of energy metabolism, signaling pathways, cell differentiation, cell proliferation and cell death. Mitochondrion with its own genetic material has characteristics distinct from those of the nuclear counterpart and its dysregulation is associated with a myriad of diseases. The discovery of interplay between the nuclear and mitochondrial genes, and various post-transcriptional modifications associated with their products has added excitement in the field. This has led to better understanding of the basic mitochondrial function in normal and disease states, and is important for diagnosis and prognosis of large number of disorders. The Fourth Annual Conference of Society for Mitochondrial Research and Medicine - India (SMRM) was titled "Mitochondrial Biology: from Molecules to Disease". The conference was organized by K. Satyamoorthy and K. Thangaraj at School of Life Sciences, Manipal University, Manipal, India, during 8-9 December, 2014. The aim of the conference was to bring researchers and clinicians to a common platform; create an opportunity for networking between laboratories; and to discuss about the recent development in mitochondrial biology, diagnosis, and therapy. This review summarizes the key outcomes of the conference.
Elastic hydrogel substrate supports robust expansion of murine myoblasts and enhances their engraftment.Sunday, July 26, 2015
Ding K, Yang Z, Xu JZ, Liu WY, Zeng Q, Hou F, Lin S,
Experimental cell research. 22-Jul-2015
The application of satellite cell-derived myoblasts in regenerative medicine has been restricted by the rapid loss of stemness during in vitro cell expansion using traditional culture systems. However, studies published in the past decade have highlighted the influence of substrate elasticity on stem cell fate and revealed that culture on a soft hydrogel substrate can promote self-renewal and prolong the regenerative potential of muscle stem cells. Whether hydrogel substrates have similar effects after long-term robust expansion remains to be determined. Herein we prepared an elastic chitosan/beta-glycerophosphate/collagen hydrogel mimicking the soft microenvironment of muscle tissues for use as the substrate for satellite cell culture and investigated its influence on long-term cell expansion. After 20 passages in culture, satellite cell-derived myoblasts cultured on our hydrogel substrate exhibited significant improvements in proliferation capability, cell viability, colony forming frequency, and potential for myogenic differentiation compared to those cultured on a routine rigid culture surface. Immunochemical staining and western blot analysis both confirmed that myoblasts cultured on the hydrogel substrate expressed higher levels of several differentiation-related markers, including Pax7, Pax3, and SSEA-1, and a lower level of MyoD compared to myoblasts cultured on rigid culture plates (all p<0.05). After transplantation into the tibialis anterior of nude mice, myoblasts that had been cultured on the hydrogel substrate demonstrated a significantly greater engraftment efficacy than those cultured on the traditional surface. Collectively, these results indicate that the elastic hydrogel substrate supported robust expansion of murine myoblasts and enhanced their engraftment in vivo.
Alginate micro-encapsulation of mesenchymal stromal cells enhances modulation of the neuro-inflammatory response.Sunday, July 26, 2015
Stucky EC, Schloss RS, Yarmush ML, Shreiber DI,
Cytotherapy. 22-Jul-2015
These results suggest that alginate encapsulation of MSCs may not only provide an improved delivery vehicle for transplantation but may also enhance MSC therapeutic benefit for treating neuro-inflammation.
Autopsy case of undiagnosed gangliocytoma in the medulla oblongata complicated with cerebral palsy.Sunday, July 26, 2015
Takahashi M, Kondo T, Morichika M, Kuse A, Nakagawa K, Asano M, Ueno Y,
Legal medicine (Tokyo, Japan). 21-Jul-2015
A Japanese man in his 30s who had congenital cerebral palsy was found unresponsive in bed. His death was confirmed after resuscitation attempts. He had a history of occasional falling (despite the use of walking sticks and a wheelchair) owing to a slowly progressive gait disturbance, and had a medical examination without full neurological re-examination. Autopsy revealed gangliocytoma in the medulla oblongata, which was diagnosed as the cause of death. Although gangliocytoma is a well-differentiated benign tumor, the almost total replacement of the medulla oblongata by the tumor cells was assumed to result in ataxia via the olivocerebellar tract and secondary cerebellar atrophy, followed by central hypoventilation and death of the patient. The symptoms caused by gangliocytoma may be overlooked owing to long-standing cerebral palsy.
CD4+ T cells in aged or thymectomized recipients of allogeneic stem cell transplantations.Monday, July 27, 2015
Takahashi H, Ikeda K, Ogawa K, Saito S, Ngoma AM, Mashimo Y, Ueda K, Furukawa M, Shichishima-Nakamura A, Ohkawara H, Nollet KE, Ohto H, Takeishi Y,
Biological research. 2015
Treg cells that modulate human allogeneic immunity may arise peripherally as well as in the thymus of allo-HSCT recipients.
Phase I/II Trial of Dose Escalated Busulfan Delivered by Prolonged Continuous Infusion in Allogeneic Transplant Patients.Sunday, July 26, 2015
Shea T, Walko C, Chung Y, Ivanova A, Sheets J, Rao K, Gabriel D, Comeau T, Wood W, Coghill J, Armistead P, Sarantopoulos S, Serody J,
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 22-Jul-2015
Intensive chemotherapy or chemotherapy plus irradiation and allogeneic stem cell transplantation can be curative for patients with hematologic diseases. Reduced intensity transplants can also achieve cure, and result in less treatment related mortality but higher relapse rates. Thus, optimizing the conditioning regimens used in allogeneic transplantation remains an important goal. We conducted a Phase I/II trial to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of a continuous infusion of busulfan over 90 hours in conjunction with fludarabine followed by allogeneic related or unrelated donor transplant. Fifty-four patients with advanced hematologic malignancies were enrolled on this study. The MTD was identified as a 24 hour area under the curve (AUC) of approximately 7095 uMmin which represents a 43% increase over the standard total daily AUC dose of 4800 uMmin given by intermittent schedules. DLTs at doses over 8000 uMmin were identified as a desquamative skin rash and mucositis. No dose-related increase in hepatic, pulmonary or other organ toxicies were seen while efficacy appeared to be improved at higher dose levels. Continuous infusion busulfan with intermittent fludarabine provides an alternative treatment strategy that is generally well tolerated and permits an increase in total busulfan dose with encouraging efficacy.
Biology of the bone marrow microenvironment and myelodysplastic syndromes.Sunday, July 26, 2015
Rankin EB, Narla A, Park JK, Lin S, Sakamoto KM,
Molecular genetics and metabolism. 20-Jul-2015
Myelodysplastic syndromes (MDS) are characterized by cytopenias resulting from ineffective hematopoiesis with a predisposition to transform to acute myeloid leukemia (AML). Recent evidence suggests that the hematopoietic stem cell microenvironment contributes to the pathogenesis of MDS. Inflammation and hypoxia within the bone marrow are key regulators of hematopoietic stem and progenitor cells that can lead to several bone marrow failure syndromes, including MDS. In this brief review, we provide an overview of the clinical and molecular features of MDS, the bone marrow microenvironment, and specific pathways that lead to abnormal blood cell development in MDS. Characterization of key steps in the pathogenesis of MDS will lead to new approaches to treat patients with this disease.
Human Induced Pluripotent Stem Cells Re-Engineer the Study of Neurodevelopmental Disorders.Monday, July 27, 2015
Kim ES, Dranovsky A,
Journal of the American Academy of Child and Adolescent Psychiatry. Aug-2015
The crucial role of vitamin C and its transporter (SVCT2) in bone marrow stromal cell autophagy and apoptosis.Sunday, July 26, 2015
Sangani R, Periyasamy-Thandavan S, Pathania R, Ahmad S, Kutiyanawalla A, Kolhe R, Bhattacharyya MH, Chutkan N, Hunter M, Hill WD, Hamrick M, Isales C, Fulzele S,
Stem cell research. 10-Jun-2015
Vitamin C is an antioxidant that plays a vital role in various biological processes including bone formation. Previously, we reported that vitamin C is transported into bone marrow stromal cells (BMSCs) through the sodium dependent Vitamin C Transporter 2 (SVCT2) and this transporter plays an important role in osteogenic differentiation. Furthermore, this transporter is regulated by oxidative stress. To date, however, the exact role of vitamin C and its transporter (SVCT2) in ROS regulated autophagy and apoptosis in BMSCs is poorly understood. In the present study, we observed that oxidative stress decreased survival of BMSCs in a dose-dependent manner and induced growth arrest in the G1 phase of the cell cycle. These effects were accompanied by the induction of autophagy, confirmed by P62 and LC3B protein level and punctate GFP-LC3B distribution. The supplementation of vitamin C significantly rescued the BMSCs from oxidative stress by regulating autophagy. Knockdown of the SVCT2 transporter in BMSCs synergistically decreased cell survival even under low oxidative stress conditions. Also, supplementing vitamin C failed to rescue cells from stress. Our results reveal that the SVCT2 transporter plays a vital role in the mechanism of BMSC survival under stress conditions. Altogether, this study has given new insight into the role of the SVCT2 transporter in oxidative stress related autophagy and apoptosis in BMSCs.
A hydrogel bioink toolkit for mimicking native tissue biochemical and mechanical properties in bioprinted tissue constructs.Sunday, July 26, 2015
Skardal A, Devarasetty M, Kang HW, Mead I, Bishop C, Shupe T, Lee SJ, Jackson J, Yoo J, Soker S, Atala A,
Acta biomaterialia. 22-Jul-2015
Advancement of bioprinting technology is limited by the availability of materials that both facilitate bioprinting logistics as well as support cell viability and function by providing tissue-specific cues. Herein we describe a modular hyaluronic acid (HA) and gelatin-based hydrogel toolbox comprised of a 2-crosslinker, 2-stage polymerization technique, and the capability to provide tissue specific biochemically and mechanically accurate signals to cells within biofabricated tissue constructs. First, we prepared and characterized several tissue-derived decellularized extracellular matrix-based solutions, which contain complex combinations of growth factors, collagens, glycosaminoglycans, and elastin. These solutions can be incorporated into bioinks to provide the important biochemical cues of different tissue types. Second, we employed combinations of PEG-based crosslinkers with varying molecular weights, geometries (linear, 4-arm, and 8-arm), and functional groups to yield hydrogel bioinks that supported extrusion bioprinting and the capability to achieve final construct shear stiffness values ranging from approximately 100 Pa to 20 kPa. Lastly, we integrated these hydrogel bioinks with a 3-D bioprinting platform, and validated their use by bioprinting primary liver spheroids in a liver-specific bioink to create in vitro liver constructs with high cell viability and measurable functional albumin and urea output. This hydrogel bioink system has the potential to be a versatile tool for biofabrication of a wide range of tissue construct types.
Nootropic Effects of Filipendula Vulgaris Moench Water Extract Fractions.Sunday, July 26, 2015
Shilova IV, Suslov NI, Amelchenko VP,
Bulletin of experimental biology and medicine. 26-Jul-2015
Nootropic activity of water extract fractions from aerial parts of Filipendula vulgaris Moench was demonstrated on the models of hermetic volume hypoxia, conditioned passive avoidance response, open field test, and forced swimming with a load. The fractions stimulated hypoxic resistance, normalized orientation and exploratory behavior, improved conditioned response reproduction during testing after hypoxic injury, and increased exercise tolerance. Fractionation of the extract led to dissociation of the effect components, which suggests that individual constituents have specifi c characteristics. Ethylacetate fraction exhibited most pronounced nootropic activity and was superior to plant extract by some characteristics. The detected effects seemed to be caused by modulation of the hippocampus activity the under the effects of phenol and triterpene compounds.
Effect of UV-photofunctionalization on oral bacterial attachment and biofilm formation to titanium implant material.Sunday, July 26, 2015
de Avila ED, Lima BP, Sekiya T, Torii Y, Ogawa T, Shi W, Lux R,
Biomaterials. 17-Jul-2015
Bacterial biofilm infections remain prevalent reasons for implant failure. Dental implant placement occurs in the oral environment, which harbors a plethora of biofilm-forming bacteria. Due to its trans-mucosal placement, part of the implant structure is exposed to oral cavity and there is no effective measure to prevent bacterial attachment to implant materials. Here, we demonstrated that UV treatment of titanium immediately prior to use (photofunctionalization) affects the ability of human polymicrobial oral biofilm communities to colonize in the presence of salivary and blood components. UV-treatment of machined titanium transformed the surface from hydrophobic to superhydrophilic. UV-treated surfaces exhibited a significant reduction in bacterial attachment as well as subsequent biofilm formation compared to untreated ones, even though overall bacterial viability was not affected. The function of reducing bacterial colonization was maintained on UV-treated titanium that had been stored in a liquid environment before use. Denaturing gradient gel-electrophoresis (DGGE) and DNA sequencing analyses revealed that while bacterial community profiles appeared different between UV-treated and untreated titanium in the initial attachment phase, this difference vanished as biofilm formation progressed. Our findings confirm that UV-photofunctionalization of titanium has a strong potential to improve outcome of implant placement by creating and maintaining antimicrobial surfaces.
In vitro study on proliferation kinetics of oral mucosal keratinocytes.Sunday, July 26, 2015
Dickhuth J, Koerdt S, Kriegebaum U, Linz C, Müller-Richter UD, Ristow O, Kübler AC, Reuther T,
Oral surgery, oral medicine, oral pathology and oral radiology. 15-Jun-2015
Data from real-time cell analysis showed an increased proliferation of adherent cells compared with those derived from the supernate. These results demonstrate the increase of the proliferation capacity by cultivation of keratinocytes derived by adhesion to extracellular matrix proteins.
Synthesis and characterization of pH-sensitive poly(itaconic acid)-poly(ethylene glycol)-folate-poly(l-histidine) micelles for enhancing tumor therapy and tunable drug release.Sunday, July 26, 2015
Sun Y, Li Y, Nan S, Zhang L, Huang H, Wang J,
Journal of colloid and interface science. 8-Jul-2015
pH responsive intracellular tumor targeting is increasingly investigated as a pathway to trigger the release of anti-tumor drugs once the drug carrier reached the unique acidic environment of the solid tumors or after the drug carrier has been taken up by cells, resulting in the localization of the micelles in the acidic endosomes and lysosomes. Poly(itaconic acid)-poly(ethylene glycol)-folate-poly(l-histidine) (PIA-PEG-FA-PHIS) was synthesized as a carrier for tumor-targeted drug delivery. The micelles were internalized by receptor-mediated endocytosis, and the combination of active targeting and triggered release resulted in apparent cytotoxicity and antitumor activity. The MTT assay showed DOX-loaded micelles had higher and obvious cytotoxicity against Hela cells at pH 5.0 than that at pH 7.4. Cellular uptake experiments revealed that these pH-responsive PIA-PEG-FA-PHIS micelles were taken up in great amounts by receptor-mediated endocytosis and delivered to lysosomes, triggering release of DOX into the cytoplasm. These indicated that the PIA-PEG-FA-PHIS micelles could be a promising drug delivery system with preeminent stability for targeting the hydrophobic drugs to cancer cells and releasing DOX in to the cells by sensing the acidic environment of the endosomes for cancer therapy.
Your questions about complementary medicines answered: glucosamine.Monday, July 27, 2015
Kreijkamp-Kaspers S, McGuire T, Bedford S, Loadsman P, Pirotta M, Moses G, van Driel ML,
Australian family physician. 2015
This is the second article in a series providing evidence-based answers to common questions about complementary medicines from consumers and healthcare professionals.
Your questions about complementary medicines answered.Monday, July 27, 2015
Kreijkamp-Kaspers S, McGuire T, Bedford S, Loadsman P, Pirotta M, Moses G, van Driel ML,
Australian family physician. 2015
This is the first article in a series providing evidence-based answers to common 
questions about complementary medicines from consumers and healthcare professionals.
Cardiogenic differentiation of mesenchymal stem cells with gold nanoparticle loaded functionalized nanofibers.Sunday, July 26, 2015
Sridhar S, Venugopal JR, Sridhar R, Ramakrishna S,
Colloids and surfaces. B, Biointerfaces. 17-Jul-2015
Cardiac tissue engineering promises to revolutionize the treatment of patients with end-stage heart failure and provide new solutions to the serious problems of shortage of heart donors. The influence of extracellular matrix (ECM) plays an influential role along with nanostructured components for guided stem cell differentiation. Hence, nanoparticle embedded Nanofibrous scaffolds of FDA approved polycaprolactone (PCL), Vitamin B12 (Vit B12), Aloe Vera(AV) and Silk fibroin(SF) was constructed to differentiate mesenchymal stem cells into cardiac lineage. Cardiomyocytes (CM) and Mesenchymal stem cells (MSC) were co-cultured on these fabricated nanofibrous scaffolds for the regeneration of infarcted myocardium. Results demonstrated that synthesized gold nanoparticles were of the size 16nm and the nanoparticle loaded nanofibrous scaffold has a mechanical strength of 2.56MPa matching that of the native myocardium. The gold nanoparticle blended PCL scaffolds were found to be enhancing the MSCs proliferation and differentiation into cardiogenesis. Most importantly the phenotype and cardiac marker expression in differentiated MSCs were highly resonated in gold nanoparticle loaded nanofibrous scaffolds. The appropriate mechanical strength provided by the functionalized nanofibrous scaffolds profoundly supported MSCs to produce contractile proteins and achieve typical cardiac phenotype.
Bio-inspired mineralization of hydroxyapatite in 3D silk fibroin hydrogel for bone tissue engineering.Sunday, July 26, 2015
Jin Y, Kundu B, Cai Y, Kundu SC, Yao J,
Colloids and surfaces. B, Biointerfaces. 17-Jul-2015
To fabricate hard tissue implants with bone-like structure using a biomimetic mineralization method is drawing much more attentions in bone tissue engineering. The present work focuses in designing 3D silk fibroin hydrogel to modulate the nucleation and growth of hydroxyapatite crystals via a simple ion diffusion method. The study indicates that Ca(2+) incorporation within the hydrogel provides the nucleation sites for hydroxyapatite crystals and subsequently regulates their oriented growth. The mineralization process is regulated in a Ca(2+) concentration- and minerlization time-dependent way. Further, the compressive strength of the mineralized hydrogels is directly proportional with the mineral content in hydrogel. The orchestrated organic/inorganic composite supports well the viability and proliferation of human osteoblast cells; improved cyto-compatibility with increased mineral content. Together, the present investigation reports a simple and biomimetic process to fabricate 3D bone-like biomaterial with desired efficacy to repair bone defects.
Pendant small functional groups on poly(ϵ-caprolactone) substrate modulate adhesion, proliferation and differentiation of human mesenchymal stem cells.Sunday, July 26, 2015
Chen M, Zhang Y, Zhou Y, Zhang Y, Lang M, Ye Z, Tan WS,
Colloids and surfaces. B, Biointerfaces. 17-Jul-2015
Probing stem cell-biomaterial interactions is of great significance in both gaining profound understanding of stem cell biology and advancing tissue regeneration. In the present work, we developed a series of poly(ϵ-caprolactone) (PCL) films bearing distinct pendant small functional groups to study the effects of biomaterial substrate chemistry on stem cell behaviors. PCL films, bearing hydroxyl (OH), methyl (CH3), carboxyl (COOH) and amino (NH2), demonstrated varied surface properties, such as wettability, serum protein adsorption and surface topographical feature. In comparison with pristine PCL film, the adhesion of hMSCs on PCL-COOH, PCL-OH and PCLCO films was significantly promoted and cells slightly outgrew on PCL-NH2 and PCL-COOH films. Most importantly, the tri-lineage differentiation of hMSCs varied on this series of PCL films, with the best osteogenesis achieved on PCL-NH2 film, PCL and PCL-CH3 films supporting the superior adipogenic differentiation and PCL-CH3 film being the most favorable one for chondrogenesis. This study highlights the critical roles of surface chemistry in modulating the fates of MSCs and potentially provides a practical guidance in developing instructive tissue engineering scaffolds.
Mesenchymal stem cells promote CD206 expression and phagocytic activity of macrophages through IL-6 in systemic lupus erythematosus.Sunday, July 26, 2015
Deng W, Chen W, Zhang Z, Huang S, Kong W, Sun Y, Tang X, Yao G, Feng X, Chen W, Sun L,
Clinical immunology (Orlando, Fla.). 22-Jul-2015
Human umbilical cord-derived mesenchymal stem cells (UCMSC) show therapeutic effects on systemic lupus erythematosus (SLE). Deficiency in functional polarization and phagocytosis in macrophages has been suggested in the pathogenesis of SLE. We found macrophages from B6.MRL-Fas(lpr) mice exhibited lower level of CD206, the marker for alternatively activated macrophage (AAM, also called M2). In addition, the phagocytic activity of B6.MRL-Fas(lpr) macrophages was also decreased. UCMSC transplantation improved the proportion of CD206(+) macrophages and their phagocytic activity in B6.MRL-Fas(lpr) mice. Importantly, macrophages from SLE patients also showed lower expression of CD206 and reduced phagocytic activity, which were corrected by co-cultured with UCMSC in vitro and in SLE patients receiving UCMSC transplantation. Mechanistically, we demonstrated that IL-6 was required for the up-regulation of CD206 expression and phagocytic activity of UCMSC-treated SLE macrophages. Our results indicate that UCMSC alleviate SLE through promoting CD206 expression and phagocytic activity of macrophages in an IL-6 dependent manner.
Neuro-peptide treatment with Cerebrolysin improves the survival of neural stem cell grafts in an APP transgenic model of Alzheimer disease.Monday, July 27, 2015
Rockenstein E, Desplats P, Ubhi K, Mante M, Florio J, Adame A, Winter S, Brandstaetter H, Meier D, Masliah E,
Stem cell research. Jul-2015
Neural stem cells (NSCs) have been considered as potential therapy in Alzheimer's disease (AD) but their use is hampered by the poor survival of grafted cells. Supply of neurotrophic factors to the grafted cells has been proposed as a way to augment survival of the stem cells. In this context, we investigated the utility of Cerebrolysin (CBL), a peptidergic mixture with neurotrophic-like properties, as an adjunct to stem cell therapy in an APP transgenic (tg) model of AD. We grafted murine NSCs into the hippocampus of non-tg and APP tg that were treated systemically with CBL and analyzed after 1, 3, 6 and 9months post grafting. Compared to vehicle-treated non-tg mice, in the vehicle-treated APP tg mice there was considerable reduction in the survival of the grafted NSCs. Whereas, CBL treatment enhanced the survival of NSCs in both non-tg and APP tg with the majority of the surviving NSCs remaining as neuroblasts. The NSCs of the CBL treated mice displayed reduced numbers of caspase-3 and TUNEL positive cells and increased brain derived neurotrophic factor (BDNF) and furin immunoreactivity. These results suggest that CBL might protect grafted NSCs and as such be a potential adjuvant therapy when combined with grafting.
REST-miR-21-SOX2 axis maintains pluripotency in E14Tg2a.4 embryonic stem cells.Saturday, July 25, 2015
Singh SK, Marisetty A, Sathyan P, Kagalwala M, Zhao Z, Majumder S,
Stem cell research. 2-Jul-2015
Our previous studies have shown that the regulatory network that maintains pluripotency in mouse embryonic stem cells (mESCs) is regulated in a context-dependent manner and can be modulated, at least in part, by re-calibration of an intracellular network of pluripotency factors as well as cues arising from the extracellular matrix. The transcriptional repressor REST represses miR-21 and, thus, regulates self-renewal in E14Tg2a.4 mESCs cultured in the absence of mouse embryonic fibroblast feeder cell effects. However, how miR-21 connects to the nuclear regulatory network has not been clear. Here, we show that miR-21, a direct target of REST-mediated repression, directly targets Sox2. Exogenously added miR-21 to mESCs decreases the expression of Sox2, decreasing mESC self-renewal, and this effect of miR-21 on mESC self-renewal can be blocked by expression of exogenous Sox2. Conversely, destabilization of Sox2 by miR-21 can be blocked by anti-miR-21. Thus, the REST-miR-21-Sox2 axis connects REST to the core nuclear pluripotency regulators in E14Tg2a.4 mESCs cultured in the absence of feeder cells.
Novel source of human hematopoietic stem cells from peritoneal dialysis effluents.Saturday, July 25, 2015
Shen J, Zheng J, Saxena R, Zhang C, Tang L,
Stem cell research. 16-Jul-2015
Hematopoietic stem cells (HSCs) hold great promise for the treatment of various diseases and blood disorders. However, limited availability of these cells has hampered their applications in clinical and biological research. Here we have identified a new source of autologous human HSCs in peritoneal dialysis (PD) effluents from patients with end stage renal diseases (ESRDs). Cells isolated from PD effluents contain a Lin(-)/CD34(+)/CD38(-)/CD90(+) sub-population and can repopulate NOD/SCID/gamma-/- mice in serial transplantation. Differing from cord blood HSCs, PD-derived HSCs have high tendencies to repopulate peritoneal cavity and spleen with myeloid cells and B lymphocytes. Repopulating HSCs also reside in peritoneal cavities in mice. The isolation of HSCs from peritoneal cavities provides a novel and promising source of autologous and functional HSCs for stem cell research and possible clinical use.
BMP4 and FGF strongly induce differentiation of mouse ES cells into oral ectoderm.Saturday, July 25, 2015
Ochiai H, Suga H, Yamada T, Sakakibara M, Kasai T, Ozone C, Ogawa K, Goto M, Banno R, Tsunekawa S, Sugimura Y, Arima H, Oiso Y,
Stem cell research. 2-Jul-2015
During embryonic development, oral ectoderm differentiates into the adenohypophysis, dental epithelia, salivary glands, and nasal pit. Few reports exist concerning the induction of oral ectoderm from embryonic stem (ES) cells. Generally, any lot differences in fetal bovine serum (FBS) and serum replacer may affect the induction of ES cell-differentiation. Using a previously established culture strategy for differentiation, the proportion of cell aggregates containing Pitx1+ oral ectoderm varied widely between 9-36% when several different lots of FBS or serum replacer were used. We therefore tried to enhance the differentiation method. We found that bone morphogenetic protein (BMP) 4 and fibroblast growth factor (FGF) treatments improved oral ectoderm induction. Such treatment also improved the differentiation of oral ectoderm into the adenohypophysis. Furthermore, increased BMP4 treatment induced dental epithelium and mesenchyme. Such differentiation suggests that the Pitx1+ layer displays similar properties to oral ectoderm, as found in vivo. Differentiation of ES cells into oral ectoderm using different lots of FBS and serum replacer increased 78-90% after treatment with BMP4 and FGF. In summary, we have established a robust strategy for the induction of oral ectoderm differentiation from mouse ES cells.
Inhibiting actin depolymerization enhances osteoblast differentiation and bone formation in human stromal stem cells.Saturday, July 25, 2015
Chen L, Shi K, Frary CE, Ditzel N, Hu H, Qiu W, Kassem M,
Stem cell research. 30-Jun-2015
Remodeling of the actin cytoskeleton through actin dynamics is involved in a number of biological processes, but its role in human stromal (skeletal) stem cells (hMSCs) differentiation is poorly understood. In the present study, we demonstrated that stabilizing actin filaments by inhibiting gene expression of the two main actin depolymerizing factors (ADFs): Cofilin 1 (CFL1) and Destrin (DSTN) in hMSCs, enhanced cell viability and differentiation into osteoblastic cells (OB) in vitro, as well as heterotopic bone formation in vivo. Similarly, treating hMSC with Phalloidin, which is known to stabilize polymerized actin filaments, increased hMSCs viability and OB differentiation. Conversely, Cytocholasin D, an inhibitor of actin polymerization, reduced cell viability and inhibited OB differentiation of hMSC. At a molecular level, preventing Cofilin phosphorylation through inhibition of LIM domain kinase 1 (LIMK1) decreased cell viability and impaired OB differentiation of hMSCs. Moreover, depolymerizing actin reduced FAK, p38 and JNK activation during OB differentiation of hMSCs, while polymerizing actin enhanced these signaling pathways. Our results demonstrate that the actin dynamic reassembly and Cofilin phosphorylation loop is involved in the control of hMSC proliferation and osteoblasts differentiation.
Nitric oxide induces hypoxia ischemic injury in the neonatal brain via the disruption of neuronal iron metabolism.Saturday, July 25, 2015
Lu Q, Harris VA, Rafikov R, Sun X, Kumar S, Black SM,
Redox biology. 23-Jun-2015
We have recently shown that increased hydrogen peroxide (H2O2) generation is involved in hypoxia-ischemia (HI)-mediated neonatal brain injury. H2O2 can react with free iron to form the hydroxyl radical, through Fenton Chemistry. Thus, the objective of this study was to determine if there was a role for the hydroxyl radical in neonatal HI brain injury and to elucidate the underlying mechanisms. Our data demonstrate that HI increases the deposition of free iron and hydroxyl radical formation, in both P7 hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD), and the neonatal rat exposed to HI. Both these processes were found to be nitric oxide (NO) dependent. Further analysis demonstrated that the NO-dependent increase in iron deposition was mediated through increased transferrin receptor expression and a decrease in ferritin expression. This was correlated with a reduction in aconitase activity. Both NO inhibition and iron scavenging, using deferoxamine administration, reduced hydroxyl radical levels and neuronal cell death. In conclusion, our results suggest that increased NO generation leads to neuronal cell death during neonatal HI, at least in part, by altering iron homeostasis and hydroxyl radical generation.
Potential alternative approaches to xenotransplantation.Saturday, July 25, 2015
Mou L, Chen F, Dai Y, Cai Z, Cooper DK,
International journal of surgery (London, England). 22-Jul-2015
There is an increasing worldwide shortage of organs and cells for transplantation in patients with end-stage organ failure or cellular dysfunction. This shortage could be resolved by the transplantation of organs or cells from pigs into humans. What competing approaches might provide support for the patient with end-stage organ or cell failure? Four main approaches are receiving increasing attention - (i) implantable mechanical devices, although these are currently limited almost entirely to devices aimed at supporting or replacing the heart, (ii) stem cell technology, at present directed mainly to replace absent or failing cells, but which is also fundamental to progress in (iii) tissue engineering and regenerative medicine, in which the ultimate aim is to replace an entire organ. A final novel potential approach is (iv) blastocyst complementation. These potential alternative approaches are briefly reviewed, and comments added on their current status and whether they are now (or will soon become) realistic alternative therapies to xenotransplantation.
Key pathways in renal disease progression of experimental diabetes.Saturday, July 25, 2015
Zoja C, Zanchi C, Benigni A,
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. Aug-2015
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes mellitus and the leading cause of end-stage kidney disease. Both diabetes and chronic kidney disease are risk factors for cardiovascular disease, and diabetic patients with renal involvement are three times more likely to eventually die of cardiovascular disease than diabetic patients without signs of renal failure. In type 2 diabetes, microalbuminuria is a marker of renal dysfunction and a crucial predictor of cardiovascular disease. Inhibitors of angiotensin II synthesis/activity, while preventing micro- or macroalbuminuria, also reduced cardiovascular events in diabetic patients. However, the effectiveness of renin angiotensin system blocking agents depends on the time when treatment is started, and imperfect renoprotection may occur if therapy begins at an advanced disease phase. This raises the need to identify novel multidrug approaches that simultaneously inhibit additional pathways other than angiotensin II for those diabetic patients who remain at high risk of both poor renal and cardiovascular outcomes. Studies in animal models of diabetes have contributed to defining relevant cellular mechanisms underlying the pathogenesis of DN that could represent possible targets for therapies. The pathogenesis of DN is multifactorial, involving a complex series of molecular processes. In this review, we report evidence obtained in experimental models of DN on some specific processes and pathways implicated in DN that may be crucial for managing this disease.
Source: NCBI - Disclaimer and Copyright notice
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