Allogeneic bone marrow-derived flk-1+Sca-1- mesenchymal stem cells leads to stable mixed chimerism and donor-specific tolerance

Objective. To investigate the possibility of flk-1(+)Sca-1(-) bone marrow-derived mesenchymal stem cells (bMSCs) to induce stable mixed chimerism and donor-specific graft tolerance. Methods. Allogeneic flk-1(+)Sca-1(-) bMSCs and syngeneic bone marrow (BM) cells were cotransplanted into lethally irradiated (8.5 Gy) recipient mice. FACS was used to analyze the chimerism 150 days later. Donor-type skin transplantation was performed to observe donor-specific immunotolerance in recipient mice. Mixed lymphocyte reaction (MLR) and mitogen proliferative assays were performed to evaluate proliferative response of splenocytes from recipient mice. Results. More than 5% donor-derived CD3(+) cells were detected in splenocytes of recipient mice. Long-term survival of donor-type skin grafts was observed. MLR and mitogen proliferative assays showed that recipient mice had low immunoresponse to donor cells but retained normal ConA-induced proliferative response compared with normal mice. Conclusion. Our results show for the first time that induction of stable mixed hematopoietic chimerism can be achieved with allogeneic flk-1(+)Sca-1(-) bMSC transplantation, which leads to permanent donor-specific immunotolerance in allogeneic host and results in long-term allogeneic skin graft acceptance. (C) 2004 International Society for Experimental Hematology. Published by Elsevier Inc.