Cited by 183Congenital heart defects researchPluripotent Stem Cells ResearchMesenchymal stem cell research

Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway

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McDevitt, Todd C., Laflamme, Michael A., Murry, Charles E.·2005·Journal of Molecular and Cellular Cardiology

Abstract

Cardiomyocytes from common experimental animals rapidly exit the cell cycle upon isolation, impeding studies of basic cell biology and applications such as myocardial repair. Here we examined proliferation of cardiomyocytes derived from human and mouse embryonic stem (ES) cells. While mouse ES cell-derived cardiomyocytes showed little proliferation, human cardiomyocytes were highly proliferative under serum-free conditions (15-25% BrdU+/sarcomeric actin+). The cells exhibited only a small serum dose-response, and proliferation gradually slowed with increasing differentiation of the cells. Neither cell density nor different matrix attachment factors affected cardiomyocyte proliferation. Blockade of phosphatidylinositol 3-kinase (PI 3-kinase) and Akt significantly reduced cardiomyocyte proliferation, whereas MEK inhibition had no effect. Antibody blocking of the insulin-like growth factor-1 (IGF-1) receptor significantly inhibited cardiomyocyte proliferation, while addition of IGF-1 or IGF-2 stimulated cardiomyocyte proliferation in a dose-dependent manner. Thus, cardiomyocytes derived from human ES cells proliferate extensively in vitro, and their proliferation appears to be mediated primarily via the PI 3-kinase/Akt signaling pathway, using the IGF-1 receptor as one upstream activator. This system should permit identification of regulatory pathways for human cardiomyocyte proliferation and may facilitate expansion of cardiomyocytes from human ES cells for therapeutic purposes.

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Crossref · 10.1016/j.yjmcc.2005.09.007

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  • The ability of hESC-CM to proliferate may compensate for cell death expected during the transition from in vitro culture to the in vivo environment.

    “Moreover, the ability of hESC-CM to proliferate (Fig. S1) (29) may compensate for cell death expected during the transition from in vitro culture to the in vivo environment.”

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Authors
McDevitt, T. C., Laflamme, M. A., & Murry, C. E.
Affiliations
University of Washington (US)
Corresponding author
  • McDevitt, Todd C.
  • Murry, Charles E.
Venue
Journal of Molecular and Cellular Cardiology
Publisher
Elsevier BV
Published
2005-12
Volume
39
Issue
6
Pages
865-873
ISSN
0022-2828 (ISSN-L)
OpenAlex
W1970947849
Cited by
183
References
41
Citations by year
2025: 2 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 9 · 2020: 11 · 2019: 8 · 2018: 4 · 2017: 8 · 2016: 8 · 2015: 7 · 2014: 12 · 2013: 16 · 2012: 7
FWCI
5.40
Type
journal article
Language
en
Open access
Locations
  • Journal of Molecular and Cellular Cardiology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r01hl064387-10)
  • National Heart, Lung, and Blood Institute (R01-HL064387, HL-64387, R01HL061553, HL61553, R24HL064387, HL3174, HL07403-25, T32HL007403, P01HL003174)
  • National Institute of General Medical Sciences (P20GM069983, GM-69983)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
cardiomyocyte proliferation, human embryonic stem cells, IGF-1 receptor, insulin-like growth factor I, insulin-like growth factor II, PI3K/Akt signaling, MEK, cell cycle exit, cardiomyocyte differentiation, myocardial repair
MeSH terms
Animals, Cells, Cultured, Dose-Response Relationship, Drug, Embryo, Mammalian, Heart Diseases, Humans, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Stem Cells, Signal Transduction, Phosphatidylinositol 3-Kinases, Myocytes, Cardiac, Cell Proliferation, Proto-Oncogene Proteins c-akt, Mice

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