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

Abstract

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 1×106 MSCs or with 1×106 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.

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

“…MIA-602 inhibited NF-κB in glioblastoma, breast cancer, and ovarian cancer (37). Most recently, MIA-602 was shown to inactivate STAT3 in mouse bone marrow-derived mesenchymal stem cells (50) and to down-regulate the expression of inflammatory cytokines in experimental ocular inflammation (38) and triplenegative breast cancer (14).…”

Reactive Oxygen Species Generation and Atherosclerosis

“…109 Recently, several publications in ATVB and other journals have demonstrated the progress in research on the role of stem/progenitor cells in atherosclerosis and oxidative stress. 13,[110][111][112][113][114] As mentioned earlier, oxidative stress response is a key event in the development of atherosclerosis, in which stem/progenitor cells sense the signal of ROS and other related species. One of the primary roles of ROS is to promote stem cell differentiation into SMCs important for both of neointimal formation after angioplasty and plaque stability.…”

Preconditioning influences mesenchymal stem cell properties in vitro and in vivo

“…Pretreatment with RU486, an antagonist of the glucocorticoid receptor, significantly increases the proliferation of human MSCs in a gender‐dependent way and enhances the expression of osteogenic markers in osteogenic MSCs compared to that observed in control MSCs . Moreover, preconditioning with JI‐34, a growth hormone‐releasing hormone agonist, enhances the differentiation into endothelial tube cells in vitro and improves the engraftment of MSCs into hemic hindlimb muscles for repairing injured parts . Although small molecules are widely used in current reprogramming programmes, they are still a negligible portion of active factors for preconditioning of MSCs, and a large number of small molecules should be developed for the protection of MSCs.…”