| Recent studies have demonstrated the tremendous differentiative potential of bone marrow (BM) mesenchymal stem cells (MSC), implicating them in repair and maintenance of various organs of the body. Given their potential, MSC have begun to be examined in many human clinical studies, and will likely prove to be an invaluable source of stem cells for future human therapies. We investigated the isolation of a population of MSC derived from human BM, fetal brain, and fetal liver tissue. Populations were isolated based upon their expression of the Stro-1 cellular surface antigen, and were shown to be capable of in vitro differentiation into mesenchymal cell lineages including osteocytes and adipocytes. We performed in vivo analysis using the large animal fetal sheep model for human stem cell transplantation. In these studies seventy-five fetal sheep received a single transplantation of human MSC derived from BM, liver, or brain. In addition to assessing the fate of each population, we also investigated the effects of altering the route of administration from the intra-peritoneal (IP) injection we have long employed to transplantation directly into the liver or brain. Studies revealed that all three populations of MSC were capable of in vivo differentiation into hematopoietic cells within the BM and peripheral blood of the sheep recipients. Upon closer examination, however, we were able to distinguish significant variations in regards to each population's differentiation potential. Liver MSC displayed the highest level of hematopoietic cell activity, possibly due to the major hematopoietic role of the fetal liver. We demonstrated that all three MSC populations transplanted by IP and direct liver injection were capable of a hepatocyte transdifferentiation, but the levels of hepatocytes varied with the tissue source of the MSC. All three MSC populations also were capable of differentiation into a population of well-described human central nervous system stem cells, with brain MSC showing the greatest efficiency. Our findings suggest that a population of MSC resides outside of the BM compartment that is capable of differentiating into cells of all three germinal layers, but shows a preference for differentiating into cells of the organ from which the MSC were derived. |
