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

Lei Yang, Mark Soonpaa, Eric D. Adler, Torsten K. Roepke, Steven J. Kattman, Marion Kennedy, Els Henckaerts, Kristina Bonham, Geoffrey W. Abbott, R. Michael Linden, Loren Field, Gordon M. Keller

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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 KDRlow/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 KDRlow/C-KITneg cells differentiate to generate populations consisting of greater than 50% contracting cardiomyocytes. Populations derived from the KDRlow/C- KITneg 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.

Original languageEnglish
Pages (from-to)524-528
Number of pages5
JournalNature
Volume453
Issue number7194
DOIs
StatePublished - May 22 2008

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Embryonic Stem Cells
Stem Cells
Fibroblast Growth Factor 2
Mesoderm
Vascular Smooth Muscle
Cardiac Myocytes
Vascular Endothelial Growth Factor A
Cell Differentiation
Bone Morphogenetic Protein 4
Population
Embryoid Bodies
Vascular Endothelial Growth Factor Receptor-2
Methylcellulose
Serum-Free Culture Media
Human Development
Smooth Muscle Myocytes
Embryonic Structures
Endothelial Cells
Clone Cells
Cell Culture Techniques

ASJC Scopus subject areas

  • General

Cite this

Yang, L., Soonpaa, M., Adler, E. D., Roepke, T. K., Kattman, S. J., Kennedy, M., ... Keller, G. M. (2008). Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. Nature, 453(7194), 524-528. https://doi.org/10.1038/nature06894

Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. / Yang, Lei; Soonpaa, Mark; Adler, Eric D.; Roepke, Torsten K.; Kattman, Steven J.; Kennedy, Marion; Henckaerts, Els; Bonham, Kristina; Abbott, Geoffrey W.; Linden, R. Michael; Field, Loren; Keller, Gordon M.

In: Nature, Vol. 453, No. 7194, 22.05.2008, p. 524-528.

Research output: Contribution to journalArticle

Yang, L, Soonpaa, M, Adler, ED, Roepke, TK, Kattman, SJ, Kennedy, M, Henckaerts, E, Bonham, K, Abbott, GW, Linden, RM, Field, L & Keller, GM 2008, 'Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population', Nature, vol. 453, no. 7194, pp. 524-528. https://doi.org/10.1038/nature06894
Yang, Lei ; Soonpaa, Mark ; Adler, Eric D. ; Roepke, Torsten K. ; Kattman, Steven J. ; Kennedy, Marion ; Henckaerts, Els ; Bonham, Kristina ; Abbott, Geoffrey W. ; Linden, R. Michael ; Field, Loren ; Keller, Gordon M. / Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population. In: Nature. 2008 ; Vol. 453, No. 7194. pp. 524-528.
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