title: Inhibition of microRNA-495 Enhances Therapeutic Angiogenesis of Human Induced Pluripotent Stem Cells.
abstract: Therapeutic angiogenesis has emerged as a promising strategy to regenerate the damaged blood vessels resulting from ischemic diseases such as myocardial infarction (MI). However, the functional integration of implanted endothelial cells (ECs) in infarcted heart remains challenging. We herein develop an EC generation approach by inhibiting microRNA-495 (miR-495) in human induced pluripotent stem cells (hiPSCs) and assess the angiogenic potential for MI treatment. The anti-angiogenic miR-495 belonging to Dlk1-Dio3 miR cluster was identified through expression profiling and computational analysis. Loss-of-function experiments for miR-495 were performed using a lentiviral transfer of antisense sequence in hiPSCs. The pluripotency of hiPSCs was not impacted by the genetic modification. Induced with differentiation medium, miR-495 inhibition enhanced the expression of EC genes of hiPSCs, as well as the yield of ECs. Newly derived ECs displayed prominent angiogenic characteristics including tube formation, cell migration, and proliferation. Mechanistically, miR-495 mediated the expression of endothelial or angiogenic genes by directly targeting vascular endothelial zinc finger 1. After transplantation in immunodeficient MI mice, the derived ECs significantly increased neovascularization in the infarcted heart, prevented functional worsening, and attenuated expansion of infarct size. The functional integration of the implanted ECs into coronary networks was also enhanced by inhibiting miR-495. miR-495 represents a new target not only for promoting EC generation from hiPSCs but also for enhancing angiogenesis and engraftment of hiPSC-derived ECs in ischemic heart. Stem Cells 2017;35:337-350.
authors.affiliation: Departments of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
authors.forename: Jialiang
authors.initials: J
authors.lastname: Liang
authors.affiliation: Departments of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Departments of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
authors.forename: Wenfeng
authors.initials: W
authors.lastname: Cai
authors.affiliation: Departments of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Departments of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
authors.forename: Linlin
authors.initials: L
authors.lastname: Guo
authors.affiliation: Departments of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Paul
authors.affiliation: Institute of Molecular and Clinical Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, China.
authors.forename: Xi-Yong
authors.initials: XY
authors.lastname: Yu
authors.affiliation: Departments of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D001483:Base Sequence; D002316:Cardiotonic Agents / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D003331:Coronary Vessels / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005810:Multigene Family; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000628:therapy; D018919:Neovascularization, Physiologic; D033581:Stem Cell Transplantation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D004268:DNA-Binding Proteins; C577768:MIRN495 microRNA, human; D035683:MicroRNAs; D014157:Transcription Factors; C088395:VEZF1 protein, human
keywords: Angiogenesis; Endothelial differentiation; Induced pluripotent stem cells; Myocardial infarction; Neovascularization; microRNAs