title: Tissue-engineered 3-dimensional (3D) microenvironment enhances the direct reprogramming of fibroblasts into cardiomyocytes by microRNAs.
abstract: We have recently shown that a combination of microRNAs, miR combo, can directly reprogram cardiac fibroblasts into functional cardiomyocytes in vitro and in vivo. Reprogramming of cardiac fibroblasts by miR combo in vivo is associated with improved cardiac function following myocardial infarction. However, the efficiency of direct reprogramming in vitro is relatively modest and new strategies beyond the traditional two-dimensional (2D) culture should be identified to improve reprogramming process. Here, we report that a tissue-engineered three-dimensional (3D) hydrogel environment enhanced miR combo reprogramming of neonatal cardiac and tail-tip fibroblasts. This was associated with significantly increased MMPs expression in 3D vs. 2D cultured cells, while pharmacological inhibition of MMPs blocked the effect of the 3D culture on enhanced miR combo mediated reprogramming. We conclude that 3D tissue-engineered environment can enhance the direct reprogramming of fibroblasts to cardiomyocytes via a MMP-dependent mechanism.
authors.affiliation: Department of Biomedical Engineering, Duke University, NC 27708, USA.
authors.forename: Yanzhen
authors.initials: Y
authors.lastname: Li
authors.affiliation: Mandel Center for Hypertension Research and Duke Cardiovascular Research Center, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Dal-Pra
authors.affiliation: Mandel Center for Hypertension Research and Duke Cardiovascular Research Center, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Mirotsou
authors.affiliation: Mandel Center for Hypertension Research and Duke Cardiovascular Research Center, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Tilanthi M
authors.initials: TM
authors.lastname: Jayawardena
authors.affiliation: Mandel Center for Hypertension Research and Duke Cardiovascular Research Center, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Conrad P
authors.initials: CP
authors.lastname: Hodgkinson
authors.affiliation: Department of Biomedical Engineering, Duke University, NC 27708, USA.
authors.forename: Nenad
authors.initials: N
authors.lastname: Bursac
authors.affiliation: Mandel Center for Hypertension Research and Duke Cardiovascular Research Center, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Dzau
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D060833:Cellular Microenvironment / Q000502:physiology*; D065150:Cellular Reprogramming / Q000187:drug effects* / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D017930:Genes, Reporter; D020100:Hydrogels; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000494:pharmacology*; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D032383:Myocytes, Cardiac / Q000166:cytology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D023822:Tissue Engineering / Q000379:methods*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection
chemical_list: D020100:Hydrogels; D035683:MicroRNAs; D009124:Muscle Proteins; D012333:RNA, Messenger; D014157:Transcription Factors