New Strategy To Improve Stem Cell Transplantation
News Nov 20, 2014
HSCI scientists at Harvard's Department of Stem Cell and Regenerative Biology and the Massachusetts General Hospital Center for Regenerative Medicine have discovered that blocking the production of a common cellular ‘glue’ (heparan sulfate) can force blood stem cells from their home in the bone marrow into the bloodstream. From there, the stem cells can be easily extracted for transplantation. Also, blocking heparan sulfate production allowed transplant recipients to accept stem cells, without the need for chemotherapy or radiation to empty out their bone marrow.
The research, done in mice and recently published in the journal Blood, raises the possibility that targeting heparan sulfate could aid future transplant-based therapies that correct genetic diseases of the blood, such as sickle cell anemia, with patients receiving their own gene-edited blood stem cells.
“We know that sickle cell anemia is a curable condition with a stem cell (bone marrow) transplant, but you don’t put people through it, in part, because of the toxicity of chemotherapy or radiation,” said David Scadden, MD, the Gerald and Darlene Jordan Professor of Medicine at Harvard University and co-chair of its Department of Stem Cell and Regenerative Biology.
“We have to figure out how to get away from these kind of sledgehammers and develop more fine-tuned tools with fewer side effects that can enable a patient’s own gene-modified blood stem cells to set up shop in their bone marrow and overcome the genetic deficiency that a person is born with,” he added. “There are certain milestones you have to hit before we get there and this is one where we’re now a step closer.”
“What we’ve found is an enzyme (glycosyltransferase) that influences how stem cells are being kept in the bone marrow,” said Borja Saez, PhD, a Scadden postdoctoral fellow and first author on the Blood paper.
“When certain skeletal stem cells don’t express this enzyme, they no longer produce functional heparan sulfate, and blood stem cells all of a sudden leave,” he said. “It is fascinating that these skeletal stem cells, which make up less than 0.1 percent of cells in the bone marrow, can influence a process as highly controlled as blood stem cell retention and egress from their native environment.”
The process of bone marrow transplantation depends upon harvesting stem cells from a donor in sufficient numbers to re-establish the entire recipient’s immune system, a process that requires the egress of stem cells from the bone marrow to the blood, a process called stem cell mobilization.
The investigators showed that inhibition of heparan sulfate with pharmacological agents made it easier to collect greater numbers of stem cells than conventional means alone. Even more important, those stem cells showed increased functionality.
“What we’ve observed with the most rigorous ways of functionally testing these cells is that different agents mobilize blood stem cells with different potencies,” said Saez. “We now have a better understanding of how to obtain more potent stem cells and this may directly impact patient care.”
The Scadden Lab plans to pursue further preclinical steps before exploring whether targeting heparan sulfate could help patients: testing a panel of agents to find the one that mobilizes the most potent stem cell pool and to test whether these agents can mobilize human cells in mouse models.
“There are a couple of parallel fronts that have to move forward before it’s possible for stem cell transplants to incorporate gene-editing,” said Scadden, who also serves as co-director of the Harvard Stem Cell Institute (HSCI) and director of the Massachusetts General Hospital (MGH) Center for Regenerative Medicine.
“One is to discover how to make the edits without creating another accidental gene modification, and the other is to find a way for people to go through a low intensity process of getting the graft to take,” he said. “We’re hoping that this research will help overcome one of these obstacles.”
Four other labs collaborated on this project, included that of: Amy Wagers, PhD, of the Harvard Department of Stem Cell and Regenerative Biology, Joslin Diabetes Center, and HSCI; Charles Lin, PhD, of Massachusetts General Hospital and HSCI; Roland Baron, DDS, PhD, of the Harvard School of Dental Medicine; and Yu Yamaguchi, MD, PhD, of the Sanford Burnham Medical Research Institute.
The work was supported by the National Institutes of Health and an American Society of Hematology Scholar Award.
Switch Discovered to Convert Blood Vessels to Blood Stem Cells During Embryonic DevelopmentNews
Findings could aid research into creating new blood cells for transplants and understanding cancer metastasis.READ MORE
Unraveling How Mesenchymal Stem Cells From Gum Tissue Accelerate Wound HealingNews
To assist with wound healing, mesenchymal stem cells from the gum tissue secrete extracellular vesicles that contain the anti-inflammatory signaling molecule IL-1RA.READ MORE