Stem Cell Subset Source of All Blood Cells, Basis of Bone Marrow Transplant Success

A new blood system isn’t created from scratch – just something close to it. A single type of stem cell, a new study demonstrates, can fully repopulate the bone marrow and give rise to all the cell lineages that constitute a complete blood system.

This blood-forming stem cell is distinguished by three cell-surface markers – or rather the presence of two markers and the absence of a third. By heeding these markers, scientists may improve transplantation procedureS, as well develop better gene therapy and gene-editing approaches.

The discovery was described in the journal Science Translational Medicine, in an article entitled “A Distinct Hematopoietic Stem Cell Population for Rapid Multilineage Engraftment in Nonhuman Primates.” According to this article, CD34-positive hematopoietic stem cells (HSCs), long considered the gold standard for stem cell therapy and transplantation of stem cell–enriched grafts, do not all contribute to multilineage engraftment. In fact, few of them do.

All the work of multilineage engraftment seems to come down to a subpopulation of CD34-positive cells. To identify this subpopulation, scientists based at the Fred Hutchinson Cancer Research Center used a robust nonhuman primate transplantation model.

“We observed a population of early-engrafting cells displaying HSC-like behavior, which persisted long-term in vivo in an autologous myeloablative transplant model in nonhuman primates,” wrote the authors of the Science Translational Medicine article. “To identify this population, we characterized the phenotype and function of defined nonhuman primate hematopoietic stem and progenitor cell (HSPC) subsets and compared these to human HSPCs.”

Ultimately, the scientists focused on a cell phenotype that is demonstrated to be highly enriched for HSCs. This phenotype – marked as CD34-positive CD45RA-negative CD90-positive – fully supported “rapid short-term recovery and robust multilineage hematopoiesis in the nonhuman primate transplant model and quantitatively predicted transplant success and time to neutrophil and platelet recovery.”

Previously, it was believed that several subtypes of blood stem cells were involved at different points in enabling a new blood system to take hold, from initial engraftment to a sustained, maintained healthy system.

“These findings came as a surprise; we had thought that there were multiple types of blood stem cells that take on different roles in rebuilding a blood and immune system,” said senior author Hans-Peter Kiem, M.D., Ph.D., Endowed Chair for Cell and Gene Therapy and director of the Stem Cell and Gene Therapy Program at Fred Hutch.

“This population does it all,” he said.

While the study was done in nonhuman primates, it shows that the newly identified cell corresponds to a subtype of human blood cell, which behaved identically when tested in vitro. Previous studies in mice report identifying such a subtype of blood stem cell, but there was no matching human version of it.

Blood stem cells are the building blocks of healthy bodies. They grow and proliferate into all the cells – T cells, B cells, platelets, and more – that constitute the blood and immune systems. Treating blood stem cells or creating healthier versions of them are a focus of the fields of gene therapy and gene editing.

But it’s been unclear which types of blood stem cells are most effective at carrying on the therapies. Finding the best cell target would mean better chances of lower side effects for patients.

“The gold standard target cell population for stem cell gene therapy is cells with the marker CD34,” said lead author Stefan Radtke, Ph.D., a research associate in the Kiem Lab at Fred Hutch. “But we used two additional markers to further distinguish the population from the other blood stem cells.”

Using three protein markers that differentiate the cells from other varieties of blood stem cells, the Fred Hutch team found that a subpopulation of about 5% of all the blood stem cells did all the work in both early recovery and sustained maintenance of the newly rebuilt system.

Tracking hundreds of thousands of cells in the blood, the researchers found that the specific stem cell group started rebuilding all different cells of the blood and immune system within 10 days of being infused in nonhuman primates undergoing transplant. A year later, they found strong molecular traces of those cells, indicating that the cells were responsible for the ongoing maintenance of the newly transplanted system.

“Our ability to track individual blood cells that developed after transplant was critical to demonstrating that these really are stem cells,” said co-author Jennifer Adair, Ph.D., assistant member at Fred Hutch and an assistant professor of medical oncology at the University of Washington, School of Medicine.

The cells potentially could make it much easier to do gene therapies for hemoglobin disorders, AIDS, and blood cancers, Kiem said. The discovery may also have important implications for hematopoietic stem cell transplantation since it may lower the risk of graft-versus-host disease, a potentially fatal condition that can occur after hematopoietic stem cell transplants for genetic diseases and blood cancers.

Ultimately, the treatment would work by isolating the subset of stem cells from a human blood sample and then engineering them in the lab to fix genetic flaws or provide disease-fighting powers. Once infused back into the patient, the cells would grow, divide, and differentiate into healthy versions of all the cells in the reconstituted system.

The research team confirmed its findings using human cells and is now working to move its findings into the clinic, with hopes to be ready to integrate them in ongoing clinical trials. The researchers are currently looking for commercial partners.