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Novel harvesting method rapidly produces superior stem cells for transplantation

December 07, 2017

A new method of harvesting stem cells for bone marrow transplantation - developed by a team of investigators from the Massachusetts General Hospital (MGH) Cancer Center and the Harvard Stem Cell Institute - appears to accomplish two goals: making the donation process more convenient and less unpleasant for donors and providing cells that are superior to those acquired by current protocols. Results of the team's studies in animal models and humans will appear in the Jan. 11 issue of Cell and are being published online today

"Our new method of harvesting stem cells requires only a single injection and mobilizes the cells needed in 15 minutes; so in the time it takes to boil an egg, we are able to acquire the number of stem cells produced by the current standard five-day protocol," says Jonathan Hoggatt, PhD, of the MGH Cancer Center)and Center for Transplantation Sciences , lead author of the Cell paper. "This means less pain, time off work and lifestyle disruption for the donor; more convenience for the clinical staff, and more predictability for the harvesting procedure."

Currently, the most common way of harvesting hematopoietic (blood system) stem cells requires donors to receive daily injections of a drug called G-CSF, which induces stem cells to pass from the bone marrow into the circulation. After five days of injections - which can produce adverse effects ranging from bone pain, to nausea and vomiting, to enlargement or rupture of the spleen - the stem cells are collected through the bone marrow donation process of apheresis, which takes four to five hours. Sometimes more than one apheresis is required to collect enough stem cells, particularly when patients with conditions like multiple myeloma or non-Hodgkin's lymphoma are donating their own cells.

Hoggatt and colleagues at MGH and other institutions have investigated ways to enhance stem cell donation for several years. In a previous collaboration with Louis Pelus, PhD, of Indiana University School of Medicine , senior author of the current study, they found that adding NSAID drugs like aspirin or ibuprofen could double the effectiveness of the standard collection protocol. But since that approach still relied on multiple injections of G-CSF, the team determined that truly significant improvement to stem cell donation required eliminating the need for G-CSF.

In other previous work, Pelus's team had found that a protein called GRO (growth regulated oncogene)-beta induced rapid movement of stem cells from the marrow into the blood in animal models. Initial experiments by the current study's team revealed that GRO-beta injections were safe and well tolerated in human volunteers but had only a modest effect in mobilizing stem cells. As a result, they tried combining administration of GRO-beta with AMD3100, a drug that is already approved to increase stem cell mobilization in combination with G-CSF, and found that simultaneous administration of both drugs rapidly produced a quantity of cells equal to that provided by the five-day G-CSF protocol.

In addition to determining the mechanisms by which combined administration of GRO-beta and AMD3100 produced enough stem cells so quickly, the team found that transplantation with these cells led to faster reconstitution of bone marrow and recovery of immune cell populations in mouse models. The stem cells produced by this procedure also show patterns of gene expression similar to those of fetal hematopoietic stem cells (HSCs), which are located in the liver, rather than the bone marrow.

"These highly engraftable hematopoietic stem cells produced by our new strategy are essentially the A+ students of bone marrow stem cells," says Hoggatt. "Finding that they express genes similar to those of fetal liver HSCs, the blood-producing cells you have before birth, suggests that they will be very good at moving into an empty bone marrow space and rapidly dividing to fill the marrow and produce blood. Now we need to test the combination in a clinical trial to confirm its safety and effectiveness in humans."

A principal faculty member at the Harvard Stem Cell Institute and an assistant professor of Medicine at Harvard Medical School, Hoggatt adds that these new, highly engraftable HSCs and the protocol that generated them represent a valuable new scientific tool that could lead to ways of engineering cells that are even better at engrafting and to methods of expanding stem cells in the laboratory rather than within the bodies of donors.

"This is an exciting time in bone marrow transplantation, as the number of diseases that can be treated or possibly even cured is increasing," he says. "With new gene therapy strategies being developed for diseases like sickle cell anemia, beta thalassemia and severe combined immunodeficiency - the 'bubble boy disease' - having enough high-quality, gene-altered cells can be a key bottleneck. Our ability to acquire highly engraftable HSCs with the GRO-beta and AMD3100 combination should significantly improve and expand the availability of those treatments."
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Hoggatt and Pelus are co-corresponding authors of the Cell paper, as is David Scadden, MD, of the MGH Center for Regenerative Medicine and the Harvard Stem Cell Institute. Additional co-authors are Bin-Kuan Chou, PhD, and Shruti Datari, MGH Center for Transplantation Sciences; Peter Kharchenko, PhD, Amir Schajnovitz, PhD, Ninib Baryawno, PhD, and Francois E. Mercier, MD, CM, MGH Center for Regenerative Medicine; Tiffany Tate, Harvard Stem Cell Institute; Pratibha Singh, PhD, Seiji Fukuda, MD, PhD, and Liqiong Liu, MD, PhD, Indiana University School of Medicine; Joseph Boyer, GlaxoSmithKline; and Jason Gardner, DPhil, MA, and Dwight Morrow, Magenta Therapeutics.

Support for this study includes National Institutes of Health grants R00 HL119559, R01 HL069669, R01 HL096305 and R01 HL131768 and support from GlaxoSmithKline and the Massachusetts Life Sciences Center. A patent application covering intellectual property described in this paper has been filed by Harvard Office of Technology Development, and Magenta Therapeutics of Cambridge, co-founded by Hoggatt and Scadden, is exploring further clinical development.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $900 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2017 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."

Massachusetts General Hospital

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