Bridging the Gap: Creating More Physiologically Relevant Human Cell Models
Cutting-edge cell models are bringing lab research closer to human biology, driving breakthroughs in disease and drug discovery.
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Human cell models may never be as good as the real thing, but we need these models to be as close as possible to understand how diseases develop and progress, and whether treatments are effective.
Cell models have long been the staple for studying cellular processes and disease mechanisms, and in drug screening, but their “two-dimensional nature and absence of interactions with other tissues and vascular perfusion means they don’t accurately reflect the complexities of the human body and its intricate interactions,” explained Professor Donald E. Ingber, faculty member and founding director of the Wyss Institute for Biologically Inspired Engineering at Harvard University.
Therefore, there is a need for more physiologically relevant cell models that better mimic what happens in the human body. Three-dimensional models allow researchers to better represent the complex tissues and cell-cell interactions taking place. This article will explore the cell models currently used by researchers to understand disease and aid drug discovery, including organoids and organs-on-chips.
Understanding women’s health with organ chips
Ingber has been using organs-on-chips (organ chips) to advance research in women’s health. He was approached by The Gates Foundation to develop models of bacterial vaginosis (BV) in vagina and cervix chips to test a live biotherapeutic product (LBP) they were hoping to develop to treat BV – a major cause of preterm birth, prenatal death and increased susceptibility to HIV and HPV – in low resource nations.
Organ chips are “microfluidic culture devices lined by multiple tissue types in organ-relevant positions with organ-relevant fluid flow and mechanical cues,” Ingber explained. Human organ chips are more physiologically relevant cell models as they “recapitulate human physiology and disease states with much higher fidelity than any other human culture model,” he continued.
Compared to conventional 2D cultures in rigid planar dishes, organ chips reconstitute tissue-tissue interfaces, immune cells and physiological mechanical cues including dynamic fluid flow, which are crucial for true clinical mimicry, Ingber said.
His work with vagina and cervix chips has shown “that we can culture healthy and dysbiotic microbiome on these chips and that they do indeed replicate inflammation and injury induced by dysbiotic microbiome, and that healthy microbiome (e.g., Lactobacillus crispatus dominated consortia) suppress these effects. So, we are using these to help test and optimize design of LBP formulations of healthy probiotic microbiome and advance their development towards the clinic.”
Ingber said organ chips can provide insight into the cellular and molecular contributors to disease that involve multiple tissue types. “In addition, we have repeatedly discovered the fluid flow and mechanical forces are major contributors to the development of many diseases (e.g., pulmonary oedema, cancer, viral infection, inflammatory bowel disease, ileus and many others),” he added.
These are important new findings that could lead to entirely new approaches for therapeutics development, Ingber said: “because there is dynamic flow, drug exposure profiles (pharmacokinetics) can be mimicked in vitro to explore effects of different drug administration regimens as well as dose-dependent efficacies and toxicities.”
Ingber’s work has also shown that it’s possible to mimic human comorbidities on chips when testing drug effects, for example, lung chips from patients with COPD are ten times more sensitive to infection by influenza than healthy chips. “This is the type of information that can not be obtained in animal models, yet it often leads to complications and failures in clinical trials,” he said.
Organoids for cardiovascular research
While organ chips replicate the dynamic physiological conditions of an organ by controlling fluid flow and cell interactions within a precisely designed microenvironment, organoids focus on recreating complex tissue structures through self-organization of stem cells.
Dr. Alexander J Ainscough, lecturer in organotypic systems in the National Heart and Lung Institute (NHLI) at Imperial College London, and part of the Imperial Organoid Facility, works with organoids to study cardiovascular disease.
Organoids are 3D multi-cellular aggregates that self-assemble into spatially organized structures. Used as models of human disease and development, they can mimic the cellular ecosystem, better model the body’s complex tissues and the interactions between them and can be used to recapitulate the pathobiology of a wide range of human diseases, including genetic disorders, infectious diseases and cancer.1
“They can be thought of as mini organs, or aspects of organs and act as a lab-based model for disease and drug testing,” Ainscough explained. “They can either be derived from adult tissue biopsies or from renewable sources, such as induced pluripotent stem cells (iPSC), and guided to become different organoid types which can resemble specific tissues in an organ. Using more complex multi-cellular environments found within organoids, we can increase our understanding of signaling cues in health and disease states. We can also begin to better understand human development by exploring how cell fate is directed and maintained.”
iPSC-derived organoids differentiate and self-organize to recapitulate the structural features and cell–cell exchanges of mature tissue, and they are becoming increasingly complex.1 Ainscough said organoids “are the next advance on 2D cultures and can complement organ chips” to make even more physiologically relevant human cell models. “Organoids can tackle certain biological questions more deeply than primary cells can because they inherently contain different cell types. We can eavesdrop into the molecular conversations between these cells to get a flavor of what’s really going on inside the organs and tissues in our bodies.” Ainscough added that “iPSCs provide us with an almost limitless supply of material, which can be biobanked and distributed to labs all over the world.”
Ainscough’s new vascular bioengineering lab at Imperial is “merging organoids and organs-on-chips to create more physiologically relevant human disease models. We are also engineering stem cells to create better organoids and better blood vessels that can be used in regenerative medicine. With stem cell therapies gathering clinical momentum, it’s feasible that within our lifetimes we could see the use of stem cell-derived organoids to fabricate tissues and even whole organs for transplant.”
Modeling the human brain
Ainscough said there have been some “very exciting advances” in brain organoids since the seminal Lancaster paper in 2013. He cited Professor Paola Arlotta of the Harvard Stem Cell Institute, whose work involves using organoids to understand how the cerebral cortex develops and how human neurodevelopmental disease emerges.
Arlotta has used iPSC-derived human brain organoids as models of neuropsychiatric diseases such as autism spectrum disorder, schizophrenia and bipolar disorder. Organoids are also a promising tool in modeling Parkinson’s disease.2,3
Organoids can also be used to model different types of brain tumors; for example, Arlotta has grown glioblastoma into long-term cultured human cortical organoids that contain the major neuroglial cell types found in the cerebral cortex to recapitulate the diversity and expression programs of malignant cell states found in patient tumors. Other work has seen the development of a neoplastic cerebral organoid (neoCOR) that recapitulates brain tumorigenesis by introducing oncogenic mutations in cerebral organoids via transposon- and CRISPR/Cas9-mediated mutagenesis.4,5
What does the future hold?
In addition to modeling disease, more physiologically relevant human cell models are needed in drug development “to drastically decrease the high failure rate and associated costs that pharmaceutical and biotechnology companies face when they attempt to bring a drug through the development pipeline and obtain regulatory approval,” explained Ingber. “A major cause of failure is the inability of preclinical animal models to successfully predict drug efficacy and toxicities in humans.”
Ingber’s work has shown that human organ chips are “so good at replicating complex human responses that they can effectively replace animal testing for particular applications.” For example, human liver chips are seven to eight times more effective than animal models at predicting drug-induced liver injury in humans, while a lymphoid follicle chip can effectively replicate vaccination responses to commercial vaccines including ones for influenza (Fluzone) and SARS-CoV-2 (Moderna and Pfizer) in vitro. “Given how the critical shortage and astronomical costs of testing vaccines on non-human primates (NHPs) was a major problem during COVID-19 and continues to slow vaccine and drug development, this one human organ chip could have huge value in the next pandemic,” he said.
Organ chips are among many new alternative methods (NAMs) that are used in experiments to understand the impact a compound or an environmental factor may have on a human’s biological system. Since the passage of the FDA Modernization Act in 2022, data gathered from NAMs can now be used in preclinical testing in the investigational new drug (IND) process.
Organ chips could also be very useful for personalized medicine “to determine any individual’s, or any human subpopulation’s, response to a particular drug, toxin or pathogen,” Ingber explained. “One could envision potentially developing a drug for a specific genetic subpopulation using their chips for both efficacy and toxicity, and then do a clinical trial in that same small subgroup. I believe that this would greatly shorten the process, decrease the cost, and increase the likelihood of success.”
However, there are still challenges to overcome. Organoids and 3D tissue constructs can be more difficult to maintain in vitro for long periods and often require tissue culture media recipes unique to a tissue, cell type or biomaterial support system. They also have difficulty forming a complex vascular network that recreates the interaction between tissue and vascular systems; a lack of oxygen and nutrients mean they are unable to survive.6,7
Meanwhile, organ chips rely on microfluidic devices, which need constructing, and a connection to tissue culture media reservoirs, tubing and pumps, making them more complex compared to organoid cultures. Scaling up organ chips for large-scale drug screening can also be difficult because of the complex microfluidic design.6
Ingber and Ainscough’s work highlights the need for more physiologically relevant human cell models and the potential that organ chips and organoids have in modeling disease. But it also shines a light on how these models could be used in the future, in developing treatments – and doing so more efficiently and inexpensively – and in personalized medicine.
