Platelet-derived growth factor-BB enhances MSC-mediated cardioprotection via suppression of miR-320 expression.
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.
Department of Pharmacology, Harbin Medical University, Harbin, China; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana;
Bing
B
Xu
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana;
Yong
Y
Luo
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana; and.
Yunlong
Y
Liu
Department of Pharmacology, Harbin Medical University, Harbin, China; Department of Biomedical Engineering, Indiana University Purdue University, Indianapolis, Indiana.
Bai-Yan
BY
Li
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana; yuewang@iu.edu.
Yue
Y
Wang
D000818:Animals; D000077214:Becaplermin; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D066298:In Vitro Techniques; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D034622:RNA Interference; D020127:Recovery of Function; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C572916:MIRN320 microRNA, human; D035683:MicroRNAs; D016755:Proto-Oncogene Proteins c-jun; D020574:Proto-Oncogene Proteins c-sis; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin
PDGF; c-Jun; hsa-miR-320b; mesenchymal stem cells