A three-member research team at Albert Einstein College of Medicine has discovered that it could increase the effectiveness of stem cell transplants, which are commonly used in patients with cancer, blood disorders or autoimmune diseases caused by defective stem cells, which produce all of the body’s blood cells. The findings, made in mice, were published today in the journal Science.
“Our research has the potential to improve the success of stem cell transplants and expand their use,” explained Ulrich Steidl, M.D., Ph.D., professor and chair of cell biology, interim director of the Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, and Edward P. Evans Professor of Myelodysplastic Syndromes at Einstein, and deputy director of the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center (MECCC).
Dr. Steidl, Einstein’s Dr. Britta Will, and Dr. Xin Gao, a former Einstein postdoctoral fellow now at the University of Wisconsin at Madison, are co-corresponding authors on the paper.
Stem cell mobilization
Stem cell transplants treat diseases in which an individual’s hematopoietic (blood-forming) stem cells have become cancerous (as in leukemia or myelodysplastic syndromes) or are too few in number (as in bone marrow failure and severe autoimmune disorders). The therapy involves infusing healthy hematopoietic stem cells collected from donors into patients. To collect these stem cells, donors are given a drug that causes the stem cells to mobilize, or escape, from their normal homes in the bone marrow and enter the blood, where the stem cells can be separated from other blood cells and then transplanted. However, the drugs used to mobilize stem cells often do not release enough of them for the transplant to be effective.
“It is normal for a small fraction of hematopoietic stem cells to leave the bone marrow and enter the bloodstream, but it is not well understood what controls this mobilization,” said Dr. Will, associate professor of oncology and medicine and Diane and Arthur B. Belfer Faculty Scholar in Cancer Research at Einstein, and co-director of the Stem Cell and Cancer Biology Research Program at MECCC. “Our research represents a fundamental advance in our knowledge and points to a new way to improve hematopoietic stem cell mobilization for clinical use.”
Monitoring of trogocytosis
The researchers suspected that variations in surface proteins on hematopoietic stem cells might influence their propensity to leave the bone marrow. In studies of hematopoietic stem cells isolated from mice, they found that a large subset of hematopoietic stem cells displayed surface proteins normally associated with macrophages, a type of immune cell. Moreover, hematopoietic stem cells with these surface proteins largely remained in the bone marrow, while those without the markers readily left the marrow when given drugs to stimulate hematopoietic stem cell mobilization.
After mixing hematopoietic stem cells with macrophages, the researchers found that some of them engaged in trogocytosis, a mechanism by which one cell type extracts membrane fractions from another cell type and incorporates them into its own membranes. Hematopoietic stem cells that expressed high levels of the protein c-Kit on their surface were able to carry out trogocytosis, causing their membranes to fill with macrophage proteins, making them much more likely to remain in the bone marrow than other hematopoietic stem cells. The findings suggest that disrupting c-Kit would prevent trogocytosis, leading to more hematopoietic stem cells being mobilized and available for transplantation.
“Trogocytosis plays a role in regulating immune responses and other cellular systems, but this is the first time that stem cells have been seen to be involved in the process. We are still searching for the exact mechanism by which HSCs regulate trogocytosis,” said Dr. Gao, an assistant professor of pathology and laboratory medicine at the University of Wisconsin-Madison, Madison, Wisconsin.
The researchers plan to further investigate this process: “Our current efforts will look at other functions of trogocytosis in HSCs, including possible roles in blood regeneration, clearance of defective stem cells, and in hematologic malignancies,” Dr. Will added.
The study originated in the laboratory of the late Dr. Paul S. Frenette, a pioneer in hematopoietic stem cell research and founding director of the Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine Research at Einstein. Other key collaborators included Dr. Randall S. Carpenter and Dr. Philip E. Boulais, both postdoctoral scientists at Einstein.
He Science The paper is titled, “Regulation of the hematopoietic stem cell pool by c-Kit-associated trogocytosis.” Other authors are Huihui Li, Ph.D., and Maria Maryanovich, Ph.D., both of Einstein, Christopher R. Marlein, Ph.D., of Einstein and FUJIFILM Diosynth Biotechnologies, Wilton, England, and Dachuan Zhang, Ph.D., of Einstein and Shanghai Jiao Tong University School of Medicine, Shanghai, China, Matthew Smith of the University of Wisconsin-Madison, and David J. Chung, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center, New York, NY.
The study was supported by grants from the National Institutes of Health (U01DK116312, R01DK056638, R01DK112976, R01HL069438, DK10513, CA230756, R01HL157948, and R35CA253127).