title: Direct reprogramming of fibroblasts into endothelial cells capable of angiogenesis and reendothelialization in tissue-engineered vessels.
abstract: The generation of induced pluripotent stem (iPS) cells is an important tool for regenerative medicine. However, the main restriction is the risk of tumor development. In this study we found that during the early stages of somatic cell reprogramming toward a pluripotent state, specific gene expression patterns are altered. Therefore, we developed a method to generate partial-iPS (PiPS) cells by transferring four reprogramming factors (OCT4, SOX2, KLF4, and c-MYC) to human fibroblasts for 4 d. PiPS cells did not form tumors in vivo and clearly displayed the potential to differentiate into endothelial cells (ECs) in response to defined media and culture conditions. To clarify the mechanism of PiPS cell differentiation into ECs, SET translocation (myeloid leukemia-associated) (SET) similar protein (SETSIP) was indentified to be induced during somatic cell reprogramming. Importantly, when PiPS cells were treated with VEGF, SETSIP was translocated to the cell nucleus, directly bound to the VE-cadherin promoter, increasing vascular endothelial-cadherin (VE-cadherin) expression levels and EC differentiation. Functionally, PiPS-ECs improved neovascularization and blood flow recovery in a hindlimb ischemic model. Furthermore, PiPS-ECs displayed good attachment, stabilization, patency, and typical vascular structure when seeded on decellularized vessel scaffolds. These findings indicate that reprogramming of fibroblasts into ECs via SETSIP and VEGF has a potential clinical application.
authors.affiliation: Cardiovascular Division, King's College London British Heart Foundation Centre, London, United Kingdom.
authors.forename: Andriana
authors.initials: A
authors.lastname: Margariti
authors.forename: Bernhard
authors.initials: B
authors.lastname: Winkler
authors.forename: Eirini
authors.initials: E
authors.lastname: Karamariti
authors.forename: Anna
authors.initials: A
authors.lastname: Zampetaki
authors.forename: Tsung-neng
authors.initials: TN
authors.lastname: Tsai
authors.forename: Dilair
authors.initials: D
authors.lastname: Baban
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.forename: Jing-Dong J
authors.initials: JD
authors.lastname: Han
authors.forename: Lingfang
authors.initials: L
authors.lastname: Zeng
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Hu
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001011:Aorta / Q000473:pathology; D015820:Cadherins / Q000235:genetics; D002454:Cell Differentiation; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D042783:Endothelial Cells / Q000166:cytology*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D000090062:Kruppel-Like Factor 4; D051379:Mice; D016513:Mice, SCID; D008957:Models, Genetic; D009389:Neovascularization, Pathologic; D011401:Promoter Regions, Genetic; D013234:Stem Cells / Q000166:cytology; D013314:Stress, Mechanical; D023822:Tissue Engineering / Q000379:methods*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D000090062:Kruppel-Like Factor 4; D000099152:Cadherin 5; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse