title: Functionality of endothelial cells and pericytes from human pluripotent stem cells demonstrated in cultured vascular plexus and zebrafish xenografts.
abstract: OBJECTIVE
  Endothelial cells (ECs), pericytes, and vascular smooth muscle cells (vSMCs) are essential for vascular development, and their dysfunction causes multiple cardiovascular diseases. Primary vascular cells for research are, however, difficult to obtain. Human-induced pluripotent stem cells (hiPSCs) derived from somatic tissue are a renewable source of ECs and vSMCs; however, their use as disease models has been limited by low and inconsistent efficiencies of differentiation and the lack of phenotypic bioassays.
  
  
  RESULTS
  Here, we developed defined conditions for simultaneous derivation of ECs and pericytes with high efficiency from hiPSCs of different tissue origin. The protocol was equally efficient for all lines and human embryonic stem cells (hESCs). The ECs could undergo sequential passage and were phenotypically indistinguishable, exhibiting features of arterial-like embryonic ECs. Moreover, hiPSC-derived ECs formed an authentic vascular plexus when cocultured with hiPSC-derived pericytes. The coculture system recapitulated (1) major steps of vascular development including EC proliferation and primary plexus remodeling, and (2) EC-mediated maturation and acquisition of contractile vSMC phenotype by pericytes. In addition, hiPSC-derived ECs integrated into developing vasculature as xenografts in zebrafish. This contrasts with more widely used ECs from human umbilical vein, which form only unstable vasculature and were completely unable to integrate into zebrafish blood vessels.
  
  
  CONCLUSIONS
  We demonstrate that vascular derivatives of hiPSC, such as ECs and pericytes, are fully functional and can be used to study defective endothelia-pericyte interactions in vitro for disease modeling and studies on tumor angiogenesis.
authors.affiliation: From the Department of Anatomy and Embryology (V.V.O., C.F., S.P.-R., F.E.v.d.H., S.M., C.L.M.) and Department of Molecular Cell Biology (V.V.O., Y.D., P.t.D.), Cancer Genomics Centre and Centre for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Valeria V
authors.initials: VV
authors.lastname: Orlova
authors.forename: Yvette
authors.initials: Y
authors.lastname: Drabsch
authors.forename: Christian
authors.initials: C
authors.lastname: Freund
authors.forename: Sandra
authors.initials: S
authors.lastname: Petrus-Reurer
authors.forename: Francijna E
authors.initials: FE
authors.lastname: van den Hil
authors.forename: Suchitra
authors.initials: S
authors.lastname: Muenthaisong
authors.forename: Peter Ten
authors.initials: PT
authors.lastname: Dijke
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mummery
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002450:Cell Communication; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation; D005786:Gene Expression Regulation; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D018919:Neovascularization, Physiologic; D020286:Pericytes / Q000378:metabolism / Q000502:physiology* / Q000637:transplantation; D010641:Phenotype; D014661:Vasoconstriction; D015027:Zebrafish
chemical_list: D015415:Biomarkers
keywords: endothelial cells; induced pluripotent stem cells; pericytes