title: MicroRNA-1 enhances the angiogenic differentiation of human cardiomyocyte progenitor cells.
abstract: Instigated by the discovery of adult cardiac progenitor cells, cell replacement therapy has become a promising option for myocardial repair in the past decade. We have previously shown that human-derived cardiomyocyte progenitor cells (hCMPCs) can differentiate into cardiomyocyte-, endothelial-, and smooth muscle-like cells in vitro, and in vivo after transplantation in a mouse model of myocardial infarction, resulting in preservation of cardiac function. However, to allow successful repopulation of the injured myocardium, it is of key importance to restore myocardial perfusion by the formation of new vasculature. Several studies have shown that microRNAs regulate vascular differentiation of different stem/progenitor cells. Here, we show that miR-1 is upregulated in hCMPCs during angiogenic differentiation. Upregulation of miR-1 enhanced the formation of vascular tubes on Matrigel and within a collagen matrix, and also increased hCMPC motility, as shown by planar and transwell migration assays. By western blot, qRT-PCR and luciferase reporter assays, miR-1 was found to directly target and inhibit the expression of sprouty-related EVH1 domain-containing protein 1 (Spred1). Knocking down Spred1 phenocopies the functional effect seen for miR-1 upregulation. Using a systems biology approach, we found that in hCMPCs, miR-1 is proposed to control a network of genes predominantly involved in angiogenesis-related processes, including the Spred1 pathway. Our data shows that by upregulation of miR-1, the angiogenic differentiation of hCMPCs can be enhanced, which may be used as a new therapeutic approach to improve the efficiency of cell-based therapy for cardiac regeneration by enhancing the formation of new vasculature.
authors.affiliation: Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Heidelberglaan 100, room G02.523, 3584 CX, Utrecht, The Netherlands.
authors.forename: Alain
authors.initials: A
authors.lastname: van Mil
authors.forename: Krijn R
authors.initials: KR
authors.lastname: Vrijsen
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Goumans
authors.forename: Corina H
authors.initials: CH
authors.lastname: Metz
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Joost P
authors.initials: JP
authors.lastname: Sluijter
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002454:Cell Differentiation / Q000502:physiology*; D002465:Cell Movement; D002478:Cells, Cultured; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D035683:MicroRNAs / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C544547:MIRN1 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C504812:SPRED1 protein, human