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

ABSTRACT: 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.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 ?L 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.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.

SUBMITTER: Ma Q

PROVIDER: S-EPMC4808467 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Ma Qunchao Q Xia Xiangyang X Tao Quanwei Q Lu Kai K Shen Jian J Xu Qiyuan Q Hu Xinyang X Tang Yaoliang Y Block Norman L NL Webster Keith A KA Schally Andrew V AV Wang Jian'an J Yu Hong H

Arteriosclerosis, thrombosis, and vascular biology 20160211 4

<h4>Objective</h4>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.<h4>Approach and results</h4>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 precond ...[more]

PMID: 26868211

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Project description:Alcohol (ALC) diminishes gonadotropin-releasing hormone (GnRH) secretion and delays puberty. Glial transforming growth factor ?1 (TGF?1) plays a role in glial-neuronal communications facilitating prepubertal GnRH secretion. We assessed the effects of acute ALC administration on TGF?1-induced GnRH gene expression in the brain preoptic area (POA) and release of the peptide from the medial basal hypothalamus (MBH). Furthermore, we assessed actions and interactions of TGF?1 and ALC on an adhesion/signaling gene family involved in glial-neuronal communications.Prepubertal female rats were administered ALC or water via gastric gavage at 7:30 am. At 9:00 am, saline or TGF?1 (100 ng/3 ?l) was administered into the third ventricle. At 3:00 pm, the POA was removed and frozen for gene expression analysis and repeated for protein assessments. In another experiment, the MBH was removed from ALC-free rats. After equilibration, tissues were incubated in Locke's medium only or medium containing TGF?1 with or without 50 mM ALC for measurement of GnRH peptide released in vitro.TGF?1 induced GnRH gene expression in the POA, and this effect was blocked by ALC. We also described the presence and responsiveness of the TGF?1 receptor in the POA and showed that acute ALC exposure not only altered the TGF?1-induced increase in TGF?-R1 protein expression but also the activation of receptor-associated proteins, Smad2 and Smad3, key downstream components of the TGF?1 signaling pathway. Assessment of an adhesion/signaling family consisting of glial receptor protein tyrosine phosphatase beta and neuronal contactin-associated protein-1 (Caspr1) and contactin showed that the neuronal components were induced by TGF?1 and that ALC blocked these effects. Finally, TGF?1 was shown to induce release of the GnRH peptide in vitro, an action that was blocked by ALC.We have demonstrated glial-derived TGF?1 induces GnRH gene expression in the POA and stimulates release of the peptide from the MBH, actions necessary for driving the pubertal process. Importantly, ALC acted at both brain regions to block stimulatory effects of TGF?1. Furthermore, ALC altered neuronal components of an adhesion/signaling family previously shown to be expressed on GnRH neurons and implicated in glial-GnRH neuronal communications. These results further demonstrate detrimental effects of ALC at puberty.

Dataset Information

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

Publications

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

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