title: Induction of vascular progenitor cells from endothelial cells stimulates coronary collateral growth.
abstract: BACKGROUND
  A well-developed coronary collateral circulation improves the morbidity and mortality of patients following an acute coronary occlusion. Although regenerative medicine has great potential in stimulating vascular growth in the heart, to date there have been mixed results, and the ideal cell type for this therapy has not been resolved.
  
  
  OBJECTIVE
  To generate induced vascular progenitor cells (iVPCs) from endothelial cells, which can differentiate into vascular smooth muscle cells (VSMCs) or endothelial cells (ECs), and test their capability to stimulate coronary collateral growth.
  
  
  RESULTS
  We reprogrammed rat ECs with the transcription factors Oct4, Klf4, Sox2, and c-Myc. A population of reprogrammed cells was derived that expressed pluripotent markers Oct4, SSEA-1, Rex1, and AP and hemangioblast markers CD133, Flk1, and c-kit. These cells were designated iVPCs because they remained committed to vascular lineage and could differentiate into vascular ECs and VSMCs in vitro. The iVPCs demonstrated better in vitro angiogenic potential (tube network on 2-dimensional culture, tube formation in growth factor reduced Matrigel) than native ECs. The risk of teratoma formation in iVPCs is also reduced in comparison with fully reprogrammed induced pluripotent stem cells (iPSCs). When iVPCs were implanted into myocardium, they engrafted into blood vessels and increased coronary collateral flow (microspheres) and improved cardiac function (echocardiography) better than iPSCs, mesenchymal stem cells, native ECs, and sham treatments.
  
  
  CONCLUSIONS
  We conclude that iVPCs, generated by partially reprogramming ECs, are an ideal cell type for cell-based therapy designed to stimulate coronary collateral growth.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH 44272, USA.
authors.forename: Liya
authors.initials: L
authors.lastname: Yin
authors.forename: Vahagn
authors.initials: V
authors.lastname: Ohanyan
authors.forename: Yuh Fen
authors.initials: YF
authors.lastname: Pung
authors.forename: Angelo
authors.initials: A
authors.lastname: Delucia
authors.forename: Erin
authors.initials: E
authors.lastname: Bailey
authors.forename: Molly
authors.initials: M
authors.lastname: Enrick
authors.forename: Kelly
authors.initials: K
authors.lastname: Stevanov
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Kolz
authors.forename: Giacinta
authors.initials: G
authors.lastname: Guarini
authors.forename: William M
authors.initials: WM
authors.lastname: Chilian
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D003097:Collateral Circulation; D003326:Coronary Circulation; D054059:Coronary Occlusion / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000637:transplantation*; D000090062:Kruppel-Like Factor 4; D051379:Mice; D016513:Mice, SCID; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D018919:Neovascularization, Physiologic; D051381:Rats; D017207:Rats, Sprague-Dawley; D044968:Regenerative Medicine / Q000379:methods; D012039:Regional Blood Flow; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013724:Teratoma / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D015415:Biomarkers; C000715468:Klf4 protein, mouse; C000715469:Klf4 protein, rat; D000090062:Kruppel-Like Factor 4; D014157:Transcription Factors
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