Researchers Uncover New Strategy To Boost Stem Cell Transplant Harvesting
Impairing a particular stem cell surface protein could improve mobilization and availability for transplantation.
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Stem cell transplants have become widely used to treat diseases such as cancer, blood disorders and autoimmune diseases where defective stem cells are the root cause. These transplants utilize donor or host hematopoietic stem cells (HSCs) collected from the bloodstream.
To harvest HSCs, donors are given a drug that causes HSCs to mobilize from the bone marrow to the blood. However, drugs used to mobilize HSCs often don’t liberate enough of them for the transplant to be effective.
Now, using mouse models, researchers from the Albert Einstein College of Medicine have discovered mechanisms that control HSC mobilization. These findings point to a new way to improve HSC mobilization for clinical use.
The results of the study were published in the journal Science.
Mobilizing the body’s stem cells
HSCs are immature cells that can develop into all types of blood cells. They exist predominantly in a specialized microenvironment within the bone marrow; however, a small fraction of their population continuously “escape” from the bone marrow to travel in the bloodstream during homeostasis or in greater numbers in response to infection.
The process of stem cell mobilization is harnessed in transplants whereby healthy HSCs harvested from donors' blood are infused into the patient. To improve the number of HSCs harvested, donors are given a drug that promotes HSC mobilization.
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Subscribe for FREE“While current pharmacologic mobilization works in many individuals, there is a substantial number of people who do not mobilize HSCs well,” Dr. Britta Will, associate professor of oncology and cell biology at the Albert Einstein College of Medicine, told Technology Networks. “This is particularly critical for individuals donating stem cells for their own treatment (e.g. myeloma) which could necessitate finding a matched donor which significantly increases the risk for graft vs host disease (mitigated by lifelong immunosuppression).”
To better understand the mechanisms governing the mobilization of HSCs the researchers analyzed the proteins expressed on the surface of HSCs isolated from mice, which they suspected might influence their propensity to exit the bone marrow.
The researchers observed that a large subset of HSCs display proteins on their cell surface typically associated with macrophages. They found that the macrophage marker-presenting HSCs were largely retained in the bone marrow, whereas stem cells without detectable macrophage marker presentation readily exited upon forced mobilization.
Will explained why certain HSCs may prefer staying in the bone marrow: “Macrophages in the bone marrow establish the microenvironment for stem cells, which rely on a stable and protected area they can reside in for decades. Being deeply embedded in the body and surrounded not only by numerous layers of cells as well as bone protects stem cells from mechanical, chemical and radiation-based cellular stress. This constant and shielded environment is key for maintaining our stem cells’ ability to initiate blood formation and the generation of > 1,011 cells on a daily basis.”
A potential new approach to improve stem cell transplants
Looking at in vitro cocultures of HSCs and macrophages, the researchers discovered that some HSCs could engage in trogocytosis – a mechanism whereby the plasma membrane fractions from one cell are extracted and incorporated into the membrane of another cell. This mechanism plays an important role in immune function, but this is the first time it has been observed in stem cells. “We believe that stem cells employ this mechanism for mounting rapid functional changes, very likely in the context of stress mitigation (such as blood loss, infection, aging and leukemia),” explained Will.
Utilizing mouse models and primary human cell-based assays, the researchers traced how the macrophage membrane material was transferred onto HSCs. They identified that HSCs expressing high levels of the protein c-Kit on their surface could carry out trogocytosis, causing their membranes to be augmented with macrophage protein, making them far more likely to stay in the bone marrow.
The findings suggest that impairing c-Kit could prevent trogocytosis, leading to more HSCs being mobilized and available for transplantation.
Future efforts will involve looking for other functions of trogocytosis in HSCs, including its potential roles in blood regeneration, elimination of defective stem cells and in hematologic malignancies. Will concluded, “The immediate next step could test c-Kit-blocking agents that should suppress trogocytosis; it remains to be determined if such a therapeutic strategy enhances HSC mobilization (which it very likely will), but we have to ensure that we can employ this in a safe manner. It will also have to be tested how interfering with trogocytosis may affect graft vs host disease.”
Dr. Britta Will was speaking to Blake Forman, Senior Science Writer for Technology Networks.
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 the Albert Einstein College of Medicine since 2016. She obtained her PhD in cell biology from the University of Freiburg, Germany and underwent training in hematology/oncology at Harvard University. With a passion for and through the lens of stem cell biology, Will’s laboratory seeks to discover novel therapeutic options for patients with myeloid malignancies. Current research concentrates on two largely uncharted territories in blood stem cell aging and leukemic stem cell maintenance – iron homeostasis and highly selective autophagy.
