Platelet-derived growth factor-BB enhances MSC-mediated cardioprotection via suppression of miR-320 expression

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 308; no. 9; pp. H980 - H989
• Main Authors: Xu, Bing, Luo, Yong, Liu, Yunlong, Li, Bai-Yan, Wang, Yue
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2015
• Subjects: Animals; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Down-Regulation; Gene expression; Humans; In Vitro Techniques; Ischemia; Mesenchymal Stem Cell Transplantation; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal Cells - metabolism; Mice; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Myocardial Reperfusion Injury - genetics; Myocardial Reperfusion Injury - metabolism; Myocardial Reperfusion Injury - pathology; Myocardial Reperfusion Injury - physiopathology; Myocardial Reperfusion Injury - surgery; Neovascularization, Physiologic - drug effects; Paracrine Communication - drug effects; Phosphorylation; Physiology; Proto-Oncogene Proteins c-jun - metabolism; Proto-Oncogene Proteins c-sis - pharmacology; Recovery of Function; RNA Interference; Signal Transduction - drug effects; Stem cells; Time Factors; Transfection; Vascular Endothelial Growth Factor A - metabolism; c-Jun; PDGF; mesenchymal stem cells; hsa-miR-320b
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00737.2014

Delivery of bone marrow-derived mesenchymal stem cells (MSCs) to myocardium protects ischemic tissue through the paracrine release of beneficial angiogenic and cytoprotective factors. Platelet-derived growth factor (PDGF)-BB, a potent mitogen of MSCs, is involved in the pathophysiology of ischemic heart disease. However, the role(s) of PDGF in MSC-mediated cardioprotection remains unknown. Here, we found that PDGF treatment of MSCs resulted in rapid activation of both Akt and ERK (central intracellular signal mediators), upregulated VEGF, and induced phosphorylation of the activator protein-1 (AP-1) transcription factor c-Jun. Examination of several microRNA genes having predicted promoter c-Jun-binding sites showed that PDGF treatment resulted in upregulation of miR-16-2 and downregulation of miRs-23b, -27b, and -320b. To examine possible PDGF augmentation of therapeutic potential, we evaluated the effects of PDGF using an ex vivo isolated mouse heart ischemia-reperfusion model. Human MSCs, with or without PDGF preconditioning, were infused into the coronary circulation of isolated mouse hearts. The hearts that received PDGF-treated MSCs exhibited a greater functional recovery compared with naïve MSC-infused hearts, following ischemia-reperfusion injury. This enhanced functional recovery was abolished by overexpression of miR-320, a microRNA we found downregulated by PDGF-activated c-Jun. Overexpression of miR-320 also resulted in upregulation of insulin-like growth factor binding protein (IGFBP) family members, suggesting PDGF "cross talk" with the mitogenic IGF signaling pathway. Collectively, we conclude that PDGF enhances MSC-mediated cardioprotection via a c-Jun/miR-320 signaling mechanism and PDGF MSC preconditioning may be an effective therapeutic strategy for cardiac ischemia.