title: Significant improvement of direct reprogramming efficacy of fibroblasts into progenitor endothelial cells by ETV2 and hypoxia.
abstract: Endothelial progenitor cell (EPC) transplantation is a promising therapy for ischemic diseases such as ischemic myocardial infarction and hindlimb ischemia. However, limitation of EPC sources remains a major obstacle. Direct reprogramming has become a powerful tool to produce EPCs from fibroblasts. Some recent efforts successfully directly reprogrammed human fibroblasts into functional EPCs; however, the procedure efficacy was low. This study therefore aimed to improve the efficacy of direct reprogramming of human fibroblasts to functional EPCs.
  
  
  
  Human fibroblasts isolated from foreskin were directly reprogrammed into EPCs by viral ETV2 transduction. Reprogramming efficacy was improved by culturing transduced fibroblasts in hypoxia conditions (5 % oxygen). Phenotype analyses confirmed that single-factor ETV2 transduction successfully reprogrammed dermal fibroblasts into functional EPCs.
  
  
  
  Hypoxia treatment during the reprogramming procedure increased the efficacy of reprogramming from 1.21 ± 0.61 % in normoxia conditions to 7.52 ± 2.31 % in hypoxia conditions. Induced EPCs in hypoxia conditions exhibited functional EPC phenotypes similar to those in normoxia conditions, such as expression of CD31 and VEGFR2, and expressed endothelial gene profiles similar to human umbilical vascular endothelial cells. These cells also formed capillary-like networks in vitro.
  
  
  
  Our study demonstrates a new simple method to increase the reprogramming efficacy of human fibroblasts to EPCs using ETV2 and hypoxia.
authors.affiliation: Laboratory of Stem Cell Research and Application, University of Science, Viet Nam National University, 227 Nguyen Van Cu, District 5, Ho Chi Minh City, Viet Nam. pvphuc@hcmuns.edu.vn.
authors.forename: Phuc
authors.initials: P
authors.lastname: Van Pham
authors.affiliation: Laboratory of Stem Cell Research and Application, University of Science, Viet Nam National University, 227 Nguyen Van Cu, District 5, Ho Chi Minh City, Viet Nam.
authors.forename: Ngoc Bich
authors.initials: NB
authors.lastname: Vu
authors.affiliation: Laboratory of Stem Cell Research and Application, University of Science, Viet Nam National University, 227 Nguyen Van Cu, District 5, Ho Chi Minh City, Viet Nam.
authors.forename: Hoa Trong
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Laboratory of Stem Cell Research and Application, University of Science, Viet Nam National University, 227 Nguyen Van Cu, District 5, Ho Chi Minh City, Viet Nam.
authors.forename: Oanh Thuy
authors.initials: OT
authors.lastname: Huynh
authors.affiliation: Laboratory of Stem Cell Research and Application, University of Science, Viet Nam National University, 227 Nguyen Van Cu, District 5, Ho Chi Minh City, Viet Nam.
authors.forename: Mai Thi-Hoang
authors.initials: MT
authors.lastname: Truong
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D066026:Endothelial Progenitor Cells / Q000378:metabolism* / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology*; D052816:Foreskin / Q000378:metabolism / Q000502:physiology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: C000597090:ETV2 protein, human; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D014157:Transcription Factors; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Direct reprogramming; ETV2; Endothelial progenitor cells; Epigenetic reprogramming; Fibroblast