Growth Hormone-Releasing Hormone and Its Analogues: Significance for MSCs-Mediated Angiogenesis.

Mesenchymal stromal cells (MSCs) are promising candidates for regenerative medicine because of their multipotency, immune-privilege, and paracrine properties including the potential to promote angiogenesis. Accumulating evidence suggests that the inherent properties of cytoprotection and tissue repair by native MSCs can be enhanced by various preconditioning stimuli implemented prior to cell transplantation. Growth hormone-releasing hormone (GHRH), a stimulator in extrahypothalamus systems including tumors, has attracted great attentions in recent years because GHRH and its agonists could promote angiogenesis in various tissues. GHRH and its agonists are proangiogenic in responsive tissues including tumors, and GHRH antagonists have been tested as antitumor agents through their ability to suppress angiogenesis and cell growth. GHRH-R is expressed by MSCs and evolving work from our laboratory indicates that treatment of MSCs with GHRH agonists prior to cell transplantation markedly enhanced the angiogenic potential and tissue reparative properties of MSCs through a STAT3 signaling pathway. In this review we summarized the possible effects of GHRH analogues on cell growth and development, as well as on the proangiogenic properties of MSCs. We also discussed the relationship between GHRH analogues and MSC-mediated angiogenesis. The analyses provide new insights into molecular pathways of MSCs-based therapies and their augmentation by GHRH analogues.

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 cell (MSC) 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 tests, critical limb ischemia was induced by femoral artery ligation. After surgery, mice received 50 µL phosphate-buffered saline or with 1×10(6) MSCs or with 1×10(6) JI-34-reconditioned MSCs. Treatment of MSCs with JI-34 improved MSC viability and mobility and markedly enhanced their capability to promote endothelial tube formation in vitro. These effects were paralleled by an increased phosphorylation and nuclear translocation of signal transducer and activator of transcription 3. In vivo, JI-34 pretreatment 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.

[Effect of poly(ADP-ribose)polymerase inhibitor combined with carbo on apoptosis of human breast cancer cells].

OBJECTIVE: To investigate the effect of poly(ADP-ribose)polymerase(PARP)inhibitor ABT888 combined with carbo on apoptosis of human breast cancer cells. METHODS: MTT was used to detect the cell viability of MDA-MB-435s cells after treatment of carbo and ABT888 with different concentration. FACS and Western-blotting were used to detect the cell apoptosis rate and apoptosis-related protein expression, respectively. RESULTS: Combined application of carbo and ABT888 significantly inhibited the proliferation of MDA-MB-435s cells, and the inhibition rates were significantly higher than that of carbo or ABT888 alone. The combination of carbo and ABT888 markedly induced cell apoptosis(26.3%±1.5%) more than carbo(18.6%±1.6%, P<0.01) and ABT888(14.7%±2.3%, P<0.01) alone. Combination of carbo and ABT888 significantly down-regulated the expression of anti-apoptosis factors Bcl-2 and up-regulated the pro-apoptosis proteins Bax and cleaved caspase-3. CONCLUSION: The combination of carbo and ABT888 can suppress the proliferation and induce apoptosis of human breast cancer DA-MB-435s cells.