Hypoxic mesenchymal stem cells engraft and ameliorate limb ischaemia in allogeneic recipients

Local injection of stem cells or endothelial progenitors directly into the ischaemic tissue remains an option for the management of arterial occlusion. Bone marrow-derived mesenchymal stem cells (MSCs) represent a promising alternative autologous cell source for ischaemic limb cell therapy. However, methods for applying MSCs in allogeneic transplantation remain to be developed. The purpose of this study was to evaluate the therapeutic potential of MSCs cultured under a different environment in ameliorating limb ischaemia in allogeneic recipients. Here, we demonstrated that hypoxic MSCs from B6 mice ameliorate limb ischaemia of Balb/c mice compared with normoxic MSCs. We also demonstrated that hypoxic MSCs have an increased ability to engraft in allogeneic recipients by reducing natural killer (NK) cytotoxicity and decrease the accumulation of host-derived NK cells when transplanted in vivo. These allogeneic hypoxic MSCs gave rise to CD31 endothelial cells and -smooth muscle actin (SMA) and desmin muscle cells, thereby enhancing angiogenesis and restoring muscle structure. Moreover, application of anti-NK antibodies together with normoxic MSCs enhanced angiogenesis and prevented limb amputation in allogeneic recipients with limb ischaemia. These results strongly suggest that hypoxic MSCs are intrinsically immunoprivileged and can serve as a universal donor cell for treating cardiovascular diseases.