| Transplantation of bone marrow-derived mesenchymal stem cells (MSCs) represents a promising strategy for treating cardiovascular disease. However, the efficiency of such therapy is limited by poor cell survival and engraftment. Growth hormone-releasing hormone (GHRH) regulates growth and development through pleiotropic actions on multiple target cell and tissue types. Here we studied the effect of the GHRH agonist, JI-34, on MSC survival and angiogenic therapy in a mouse model of critical limb ischemia. Treatment of MSCs with JI-34 improved MSC viability and mobility and markedly enhanced endothelial tube formation in vitro. These effects were paralleled by increased phosphorylation and nuclear translocation of STAT3. In vivo, JI-34 pre-treatment enhanced the engraftment of MSCs into ischemic hindlimb muscles and augmented reperfusion and limb salvage compared with untreated MSCs. Significantly more vasculature and proliferating CD31+ and CD34+ cells were detected in ischemic muscles that received MSCs treated with JI-34. Our studies demonstrate a novel role for JI-34 to markedly improve therapeutic angiogenesis in hindlimb ischemia by increasing the viability and mobility of MSCs. These findings support additional studies to explore the full potential of GHRH agonists to augment cell therapy in the management of ischemia. |
