TRANSPLANTATION OF ALLOGENEIC MESENCHYMAL STEM CELLS

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DESCRIPTION: (Applicant's Abstract) Human bone marrow contains mesenchymal (stromal) progenitors (human mesenchymal stem cells, hMSCs) that give rise to adventitial cells in the marrow micro environment capable of differentiating along the various mesenchymal lineages, such osteogenic, chondrogenic, adipogenic, myogenic, and perhaps to astroglial cells in CNS. These stromal progenitors can be readily isolated from bone marrow, and selectively expanded in vitro into a uniform population of stromal cells, without losing their multi-lineage potential. The applicant has recently shown that intravenous infusion of culture-expanded hMSC into humans at the time of autologous stem cell transplantation is feasible, safe, and may be associated with rapid hematopoietic engraftment. In vivo distribution and biologic function of culture-expanded hMSCs are not well understood at the present time. Recipients of allogeneic bone marrow transplantation were shown to regenerate their marrow stroma mainly from host-type cells, and preliminary data from the applicant also show that recipient hMSCs are not donor-origin. The applicant hypothesizes that this is due to low number or absence of stromal precursors within the hematopoietic stem cell graft that patients receive. In this application he plans to test whether partial allogeneic stromal engraftment can be achieved in patients already stably engrafted with donor type hematopoietic cells by infusion of 1-5 x 10(6)/kg culture expanded donor hMSCs. In a phase I clinical trial he will study patients with genetic disorders who underwent allogeneic stem cell transplantation for the correction of their disorder. He will utilize genetic and phenotypic differences between patients and donors to study marrow distribution of normal allogeneic hMSCs. In addition he will determine if there is any clinical benefit derived from normal hMSCs. His specific aims are to determine whether allogeneic culture expanded hMSCs can be safely infused into patients who had previously undergone allogeneic transplantation with same donors' hematopoietic cells and whether allogeneic hMSCs can be detected in the host marrow following their intravenous infusion. This project will allow him to learn transplantation biology of hMSCs in humans and expand its therapeutic development into allogeneic setting.