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01.Hematopoietic Stem Cells: Potential New Applications for Translational Medicine
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Hematopoietic Stem Cells: Potential New Applications for Translational Medicine $45.00
Authors:  Hady Felfly and Gabriel G. Haddad
Abstract:
Hematopoietic stem cells (HSC) are multipotent cells that produce the various lineages of blood and HSC transplantations (HSCT) are widely used to reconstitute damaged bone marrow (BM). Over time, HSCT has evolved for the treatment of non-blood diseases as well, brain in particular. However, HSCT required total myeloablation through irradiation and/or chemotherapy for the treatment of BM-related diseases, and HSCs are difficult to safely deliver in large amounts into the brain. In blood disorders, for a minimal myelosuppression to be sufficient and allow donor cells to engraft, it is necessary to determine the minimal percentage of normal BM cells needed to achieve phenotypic correction. Recent studies on animal models of â-thalassemia and sickle cell disease (SCD), through Competitive Repopulation Assay (CRA) following lethal irradiation of recipients, demonstrated that an average of 25% normal BM cells allows the production of enough normal red blood cells to significantly correct the â-thalassemia and SCD phenotypes, at the levels of BM, blood, histology, and survival, with normal donor cells contributing to 50-60% of peripheral red blood cells. Further assays using mild myelosuppression showed that long term sustained phenotypic correction can be obtained for both diseases through a novel transplantation strategy based on modulating four parameters: dose of irradiation/myelosuppression, number of transplanted cells, timing of cell injections, and number of cell doses. Through a minimal dose of irradiation of 1Gy (100 Rads) or 2Gy, two injections of BM cells within the first 24h after myelosuppression resulted in engraftment in 100% of mice and a sustained therapeutic mixed chimerism in â-thalassemia, while three to four injections were needed to achieve a similar outcome in SCD. Following the success of these trials, we modified this novel HSCT strategy and applied it to determine whether we can protect mice from lethal stroke induced through the Middle Cerebral Artery Occlusion (MCAO). Ischemia/reperfusion resulted in a major infarct that propagated over time to encompass ~70% of the affected hemisphere. When two doses of HSCs were injected at 2h and 24h after the reperfusion, 40% of mice survived, visible neurological defects disappeared, and the infarct size was reduced by two to four fold. Histological examination of brains in surviving mice revealed very few donor cells in the recipient brains, decreased total neurons count and increased glial cell numbers. These data suggest that the neuro-protection was not dependent on cell-supplementation, but rather the protection is manifested likely through growth factor secretion. Combined, these studies create a novel HSCT approach that has proved efficient for the treatment of various disorders. A “window of opportunity” exists for each disease where the donor cells should be administered, and multiple injections of donor HSCs can rescue diseases that would otherwise not be treatable. We hypothesize that the initial injection primes the affected tissue, and subsequent ones help in repair. This new strategy has opened the way for a new era of HSCT for the potential treatments and possibly cures of many diseases. 


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Hematopoietic Stem Cells: Potential New Applications for Translational Medicine