ABSTRACT
Bone marrow-derived mesenchymal stem cells (bMSCs) can differentiate into a number of different cell/tissue types, and also possess immunoregulatory functions. The present study was undertaken to elucidate the exact immunoregulatory effects of allogeneic bMSCs on T- and B-lymphocyte proliferation, activation, and function maturation of BXSB mice, which has been considered as a experimental model for human systemic lupus erythematosus (SLE). We determined that bMSCs from BALB/c mice had inhibitory effects on BXSB mice T-lymphocyte proliferation, but no inhibitory effect on their activation. In addition, they had a significant inhibitory and stimulatory effect on IL-4- and IFN-gamma-producing T cells, respectively. Also, bMSCs had inhibitory effects on the proliferation, activation, and IgG secretion of B lymphocytes. In addition, BALB/c bMSCs had an enhancing effect on CD40 expression and inhibitory effects on CD40 ligand (CD40L) ectopic hyperexpression on B cells from BXSB mice.
Subject(s)
B-Lymphocytes/immunology , Bone Marrow Cells/cytology , Mesenchymal Stem Cells/immunology , T-Lymphocytes/immunology , Transplantation, Homologous/immunology , Animals , B-Lymphocytes/cytology , B-Lymphocytes/drug effects , CD40 Antigens/metabolism , CD40 Ligand/metabolism , Cell Proliferation/drug effects , Cells, Cultured , Coculture Techniques , Concanavalin A/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Flow Cytometry , Genetic Markers/drug effects , Immunoglobulin G/metabolism , Interferon-gamma/metabolism , Interleukin-4/metabolism , Lipopolysaccharides/pharmacology , Lupus Erythematosus, Systemic/immunology , Lymphocyte Activation/drug effects , Mice , Mice, Inbred BALB C , Mice, Mutant Strains , Mitogens/pharmacology , Spleen/cytology , T-Lymphocytes/cytology , T-Lymphocytes/drug effectsABSTRACT
Stem cell plasticity has created great interest because of its potential therapeutic application in degenerative or inherited diseases. Transplantation of bone marrow-derived stem cells was shown to give rise to cells of muscle, liver, nerve, endothelium, epithelium, and so on. But there are still disputes about stem cell plasticity, especially concerning the contribution of bone marrow-derived cells to skin cells. In this study, CM-DiI fluorescence-labeled Flk-(1+) bone marrow mesenchymal stem cells (bMSCs) of BALB/c mice (H-2Kd, white) were transplanted into lethally irradiated C57BL/6 mice (H-2Kb, black). By fluorescence tracing, we found that donor cells could migrate and take residency at the skin, which was confirmed by Y chromosome-specific PCR and Southern blot. The recipient mice grew white hairs about 40 days later and white hairs could spread over the body. Immunochemistry staining and RT-PCR demonstrated that skin tissue within the white hair regions was largely composed of donor-derived H-2Kd cells, including stem cells and committed cells. Furthermore, most skin cells cultured from white hair skin originated from the donor. Thus, our findings provide direct evidence that bone marrow-derived cells can give rise to functional skin cells and regenerate skin tissue. These may have important scientific implications in stem cell biology and transplantation therapy for skin tissue injury.
Subject(s)
Bone Marrow Cells/cytology , Mesenchymal Stem Cells/cytology , Skin/cytology , Stem Cell Transplantation , Vascular Endothelial Growth Factor Receptor-2/metabolism , Animals , Cells, Cultured , Female , Graft Survival , Male , Mesenchymal Stem Cells/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Radiation Injuries, Experimental , Time Factors , Whole-Body IrradiationABSTRACT
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.
