Profound Actions of an Agonist of Growth Hormone–Releasing Hormone on Angiogenic Therapy by Mesenchymal Stem Cells

OBJECTIVE: The efficiency of cell therapy is limited by poor cell survival and engraftment. Here we studied the effect of the growth hormone-releasing hormone agonist, JI-34, on mesenchymal stem cells (MSCs) survival and angiogenic therapy in a mouse model of critical limb ischemia. APPROACH AND RESULTS: Mouse bone marrow-derived MSCs were incubated with or without 10(−8) mol/L JI-34 for 24 hours. MSCs were then exposed to hypoxia and serum deprivation to detect the effect of preconditioning on cell apoptosis, migration and tube formation. For in vivo, critical limb ischemia was induced by femoral artery ligation. After surgery, mice were received 50μl phosphate buffer saline or with 1×10(6) MSCs or with 1×10(6) JI-34 preconditioned MSCs. Treatment of MSCs with JI-34 improved MSCs viability and mobility and markedly enhanced their capability to promote 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. CONCLUSIONS: 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 Growth hormone-releasing hormone agonists to augment cell therapy in the management of ischemia