New strategies to boost stem cell harvest for transplantation

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Stem cell transplants have become widely used to treat diseases such as cancer, blood disorders, and autoimmune disorders that have a defective stem cell as their underlying cause. These transplants use donor or host hematopoietic stem cells (HSCs) harvested from the bloodstream.

To harvest HSCs, donors are given drugs that mobilize HSCs from the bone marrow into the blood, but the drugs used to mobilize HSCs often do not liberate enough HSCs for the transplant to be effective.

Now, researchers at Albert Einstein College of Medicine have used a mouse model to discover the mechanisms that control HSC mobilization. These findings point to new ways to improve HSC mobilization for clinical use.

The findings were published in the journal. Science.

Mobilizing stem cells in the body

HSCs are immature cells that can develop into any type of blood cell. They reside primarily in a specialized microenvironment within the bone marrow, although a small percentage of the population continually “escapes” the bone marrow and migrates into the bloodstream during homeostasis or in large numbers in response to infection.

The process of stem cell mobilization is used in transplants, where healthy HSCs are harvested from a donor's blood and infused into the patient. To increase the number of HSCs harvested, the donor is given drugs that promote HSC mobilization.

“Current pharmacological mobilization methods work for many people, but there is a significant number of individuals who are unable to successfully mobilize their HSCs.” Dr. Britta Willis an associate professor of oncology and cell biology at the Albert Einstein College of Medicine. Technology Network“This is particularly important for individuals donating stem cells for their own treatment (e.g., myeloma), where a compatible donor must be found and there can be a significantly increased risk of graft-versus-host disease (mitigated by lifelong immunosuppression).”

To better understand the mechanisms that control HSC migration, the researchers analyzed a protein expressed on the surface of HSCs isolated from mice, which they suspected might influence their tendency to leave the bone marrow.

The researchers observed that the majority of HSCs displayed proteins on their cell surface that are normally associated with macrophages, and found that HSCs that displayed macrophage markers were primarily retained in the bone marrow, whereas stem cells with no detectable macrophage marker presentation were quickly expelled from the bone marrow when forcibly mobilized.

Will explains why certain HSCs prefer to remain in the bone marrow: “Macrophages in the bone marrow establish the stem cell microenvironment. Stem cells depend on a stable, protected area in which they can exist for decades. Embedded deep within the body and surrounded by numerous layers of cells as well as bone, stem cells are protected from mechanical, chemical and radiation-induced cellular stresses. This constant, protected environment is key to stem cells' ability to initiate hematopoiesis and generate more than 1,011 cells every day.”

New approaches to improve stem cell transplants

Look In vitro The researchers found that in co-cultures of hematopoietic stem cells and macrophages, some hematopoietic stem cells could undergo trogocytosis, a mechanism by which a cell membrane fraction is extracted from one cell and incorporated into the cell membrane of another. This mechanism plays an important role in immune function, but this is the first time it has been observed in stem cells. “We think that stem cells use this mechanism to undergo rapid functional changes in the context of stress relief (blood loss, infection, aging, leukemia, etc.),” ​​Will explained.

Utilizing mouse models and human primary cell-based assays, The researchers traced how macrophage membrane material was transferred to HSCs, finding that HSCs expressing high levels of the protein c-Kit on their surface underwent trogocytosis, enriched their membranes with macrophage proteins, and were much more likely to remain in the bone marrow.

The findings suggest that inhibiting c-Kit may prevent trogocytosis, allowing more HSCs to be recruited and available for transplantation.

Future efforts include investigating other functions of trogocytosis in HSCs, such as blood regeneration, elimination of defective stem cells, and potential roles in hematological malignancies. Will concluded, “An immediate next step could be to test c-Kit inhibitors to suppress trogocytosis. We don't yet know if such a therapeutic strategy would enhance HSC mobilization (it very likely would), but we need to ensure that this is safe to use. We also need to test what impact disrupting trogocytosis has on graft-versus-host disease.”

Dr. Britta Will spoke with Blake Forman, Senior Science Writer at Technology Network.

reference: Gao X, Carpenter RS, Boulais PE, et al. “Regulation of the hematopoietic stem cell pool by c-Kit-associated trogocytosis.” Science.385(6709):eadp2065.doi: 10.1126/Science.adp2065

About the interviewee:

credit: Albert Einstein College of Medicine.

Dr. Britta Will has been a group leader at Albert Einstein College of Medicine since 2016. She received her PhD in Cell Biology from the University of Freiburg, Germany, and trained in Hematology/Oncology at Harvard University. Dr. Will's lab aims to discover new therapeutic options for patients with myeloid malignancies, using her passion and stem cell biology perspective. Her current research focuses on the largely uncharted territory of iron homeostasis and highly selective autophagy in blood stem cell aging and leukemic stem cell maintenance.