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Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population

Item Type:Article
Title:Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population
Creators Name:Yang, L. and Soonpaa, M.H. and Adler, E.D. and Roepke, T.K. and Kattman, S.J. and Kennedy, M. and Henckaerts, E. and Bonham, K. and Abbott, G.W. and Linden, R.M. and Field, L.J. and Keller, G.M.
Abstract:The functional heart is comprised of distinct mesoderm-derived lineages including cardiomyocytes, endothelial cells and vascular smooth muscle cells. Studies in the mouse embryo and the mouse embryonic stem cell differentiation model have provided evidence indicating that these three lineages develop from a common Flk-1(+) (kinase insert domain protein receptor, also known as Kdr) cardiovascular progenitor that represents one of the earliest stages in mesoderm specification to the cardiovascular lineages. To determine whether a comparable progenitor is present during human cardiogenesis, we analysed the development of the cardiovascular lineages in human embryonic stem cell differentiation cultures. Here we show that after induction with combinations of activin A, bone morphogenetic protein 4 (BMP4), basic fibroblast growth factor (bFGF, also known as FGF2), vascular endothelial growth factor (VEGF, also known as VEGFA) and dickkopf homolog 1 (DKK1) in serum-free media, human embryonic-stem-cell-derived embryoid bodies generate a KDR(low)/C-KIT(CD117)(neg) population that displays cardiac, endothelial and vascular smooth muscle potential in vitro and, after transplantation, in vivo. When plated in monolayer cultures, these KDR(low)/C-KIT(neg) cells differentiate to generate populations consisting of greater than 50% contracting cardiomyocytes. Populations derived from the KDR(low)/C-KIT(neg) fraction give rise to colonies that contain all three lineages when plated in methylcellulose cultures. Results from limiting dilution studies and cell-mixing experiments support the interpretation that these colonies are clones, indicating that they develop from a cardiovascular colony-forming cell. Together, these findings identify a human cardiovascular progenitor that defines one of the earliest stages of human cardiac development.
Keywords:Activins, Bone Morphogenetic Protein 4, Cardiac Myocytes, Cell Differentiation, Cell Line, Embryonic Stem Cells, Fibroblast Growth Factor 2, Intercellular Signaling Peptides and Proteins, Patch-Clamp Techniques, Proto-Oncogene Proteins c-kit, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2
Publisher:Nature Publishing Group (U.K.)
Page Range:524-528
Date:22 May 2008
Official Publication:https://doi.org/10.1038/nature06894
PubMed:View item in PubMed

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