Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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.”
From Proangiogenic scaffolds as functional templates for cardiac tissue engineering (2010) · cites this paper as [29]
Cites
Embryonic Stem Cell Lines Derived from Human Blastocysts
Thomson, J. A., Itskovitz‐Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., & Jones, J. M. (1998) · Science · doi:10.1126/science.282.5391.1145 · Cited by 15,947 · see citing works
Feeder-free growth of undifferentiated human embryonic stem cells
Xu, C., Inokuma, M. S., Denham, J., Golds, K., Kundu, P., Gold, J. D., & Carpenter, M. K. (2001) · Nature Biotechnology · doi:10.1038/nbt1001-971 · Cited by 1,872 · see citing works
Kehat, I., Kenyagin‐Karsenti, D., Snir, M., Segev, H., Amit, M., Gepstein, A., Livne, E., Binah, O., Itskovitz‐Eldor, J., & Gepstein, L. (2001) · Journal of Clinical Investigation · doi:10.1172/jci12131 · Cited by 1,814 · see citing works
Claycomb, W. C., Lanson, N. A., Stallworth, B. S., Egeland, D. B., Delcarpio, J. B., Bahinski, A., & Izzo, N. J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.6.2979 · Cited by 1,546 · see citing works
Characterization and Enrichment of Cardiomyocytes Derived From Human Embryonic Stem Cells
Xu, C., Police, S., Rao, N., & Carpenter, M. K. (2002) · Circulation Research · doi:10.1161/01.res.0000035254.80718.91 · Cited by 902 · see citing works
Fujio, Y., Nguyen, T. U., Wencker, D., Kitsis, R. N., & Walsh, K. (2000) · Circulation · doi:10.1161/01.cir.101.6.660 · Cited by 846 · see citing works
Matsui, T., Tao, J., del Monte, F., Lee, K.-H., Li, L., Picard, M. H., Force, T. L., Franke, T. F., Hajjar, R. J., & Rosenzweig, A. (2001) · Circulation · doi:10.1161/01.cir.104.3.330 · Cited by 701 · see citing works
The conserved phosphoinositide 3‐kinase pathway determines heart size in mice
Shioi, T., Kang, P., Douglas, P., Hampe, J., Yballe, C., Lawitts, J., Cantley, L., & Izumo, S. (2000) · EMBO Journal · doi:10.1093/emboj/19.11.2537 · Cited by 646 · see citing works
Akt/Protein Kinase B Promotes Organ Growth in Transgenic Mice
Shioi, T., McMullen, J., Kang, P., Douglas, P., Obata, T., Franke, T. F., Cantley, L., & Izumo, S. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.8.2799-2809.2002 · Cited by 544 · see citing works
McMullen, J. R., Shioi, T., Zhang, L., Tarnavski, O., Sherwood, M. C., Kang, P. M., & Izumo, S. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1934654100 · Cited by 534 · see citing works
Cardiomyocyte Cell Cycle Regulation
Pasumarthi, K. B. S., & Field, L. J. (2002) · Circulation Research · doi:10.1161/01.res.0000020201.44772.67 · Cited by 469 · see citing works
McMullen, J. R., Shioi, T., Huang, W., Zhang, L., Tarnavski, O., Bisping, E. H., Schinke, M., Kong, S. W., Sherwood, M. C., Brown, J. S., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m310405200 · Cited by 403 · see citing works
Matsui, T., Li, L., del Monte, F., et al. (1999) · Circulation · doi:10.1161/01.cir.100.23.2373 · Cited by 385 · see citing works
Snir, M., Kehat, I., Gepstein, A., Coleman, R., Itskovitz‐Eldor, J., Livne, E., & Gepstein, L. (2003) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00020.2003 · Cited by 336 · see citing works
Krzysztof Reiss, F., Cheng, W. N., Ferbér, A., Kajstura, J., Li, P., Li, B., Olivetti, G., Homcy, C. J., Baserga, R., & Anversa, P. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.16.8630 · Cited by 292 · see citing works
Genetic Dissection of Cardiac Growth Control Pathways
MacLellan, W. R., & Schneider, M. D. (2000) · Annual Review of Physiology · doi:10.1146/annurev.physiol.62.1.289 · Cited by 289 · see citing works
Regulation of Cardiomyocyte Apoptotic Signaling by Insulin-like Growth Factor I
Wang, L., Ma, W., Markovich, R. P., Chen, J., & Wang, P. H. (1998) · Circulation Research · doi:10.1161/01.res.83.5.516 · Cited by 288 · see citing works
Sauer, H., Rahimi, G., Hescheler, J., & Wartenberg, M. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01747-6 · Cited by 243 · see citing works
Chen, T. H.-P., Chang, T.-C., Kang, J., Choudhary, B., Makita, T., Tran, C. M., Burch, J. B. E., Eid, H. M., & Sucov, H. M. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0796 · Cited by 235 · see citing works
Stuckmann, I., Evans, S., & Lassar, A. B. (2003) · Developmental Biology · doi:10.1016/s0012-1606(02)00078-7 · Cited by 199 · see citing works
Delaughter, M. C., Taffet, G. E., Fiorotto, M. L., Entman, M. L., & Schwartz, R. J. (1999) · The FASEB Journal · doi:10.1096/fasebj.13.14.1923 · Cited by 162 · see citing works
Potential of embryonic stem cells
Wobus, A. M. (2001) · Molecular Aspects of Medicine · doi:10.1016/s0098-2997(01)00006-1 · Cited by 154 · see citing works
Welch, S., Plank, D. M., Witt, S. A., et al. (2002) · Circulation Research · doi:10.1161/01.res.0000013780.77774.75 · Cited by 148 · see citing works
Wu, W., Lee, W.-L., Wu, Y. Y., Chen, D., Liu, T.-J., Jang, A., Sharma, P. M., & Wang, P. H. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004108200 · Cited by 139 · see citing works
Sundgren, N. C., Giraud, G. D., Schultz, J. M., Lasarev, M. R., Stork, P. A., & Thornburg, K. L. R. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00232.2003 · Cited by 131 · see citing works
Steinhelper, M. E., Lanson, N. A., Dresdner, K. P., et al. (1990) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1990.259.6.h1826 · Cited by 101 · see citing works
Katz, E. B., Steinhelper, M. E., Delcarpio, J. B., et al. (1992) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1992.262.6.h1867 · Cited by 94 · see citing works
Differentiation of Cardiomyocytes in Floating Embryoid Bodies is Comparable to Fetal Cardiomyocytes
Doevendans, P. A., Kubalak, S. W., An, R.-H., et al. (2000) · Journal of Molecular and Cellular Cardiology · doi:10.1006/jmcc.2000.1128 · Cited by 89 · see citing works
Sauer, H., Neukirchen, W., Rahimi, G., Grünheck, F., Hescheler, J., & Wartenberg, M. (2003) · Experimental Cell Research · doi:10.1016/j.yexcr.2003.10.032 · Cited by 81 · see citing works
Kajstura, J., Cheng, W. N., Reiss, K., et al. (1994) · Experimental Cell Research · doi:10.1006/excr.1994.1343 · Cited by 67 · see citing works
DNA synthesis and multinucleation in embryonic stem cell-derived cardiomyocytes
Klug, M. G., Soonpaa, M. H., & Field, L. J. (1995) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1995.269.6.h1913 · Cited by 61 · see citing works
Hornberger, L. K., Singhroy, S., Cavallé-Garrido, T., et al. (2000) · Circulation Research · doi:10.1161/01.res.87.6.508 · Cited by 59 · see citing works
Cheng, W. N., Reiss, K., Kajstura, J., et al. (1995) · PubMed · Cited by 50 · see citing works
Huttenbach, Y., Ostrowski, M. L., Thaller, D. J., et al. (2001) · Cardiovascular Pathology · doi:10.1016/s1054-8807(01)00065-5 · Cited by 48 · see citing works
Rybkin, I. I., Markham, D. W., Yan, Z., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213102200 · Cited by 47 · see citing works
Klinz, F., Bloch, W., Addicks, K., & Hescheler, J. (1999) · Experimental Cell Research · doi:10.1006/excr.1998.4309 · Cited by 46 · see citing works
Epidermal Growth Factor Promotes a Cardiomyoblastic Phenotype in Human Fetal Cardiac Myocytes
Goldman, B., Mach, A., & WURZEL, J. M. (1996) · Experimental Cell Research · doi:10.1006/excr.1996.0322 · Cited by 31 · see citing works
Effects of subcultivation and culture medium on differentiation of human fetal cardiac myocytes
Goldman, B., & WURZEL, J. M. (1992) · In Vitro Cellular & Developmental Biology - Animal · doi:10.1007/bf02631014 · Cited by 25 · see citing works
Quantitative study of the myocardium in human embryos
Mandarim‐de‐Lacerda, C. A., dos Santos, M. B., & Pessanha, M. G. (1995) · Annals of Anatomy - Anatomischer Anzeiger · doi:10.1016/s0940-9602(11)80071-3 · Cited by 13 · see citing works
Xavier-Vidal, R., & Mandarim‐de‐Lacerda, C. A. (1995) · PubMed · Cited by 13 · see citing works
Culture and characterization of fetal human atrial and ventricular cardiac muscle cells
Claycomb, W. C., Delcarpio, J. B., Guice, S. E., et al. (1989) · In Vitro Cellular & Developmental Biology - Plant · doi:10.1007/bf02621262 · Cited by 10 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Biowire: a platform for maturation of human pluripotent stem cell–derived cardiomyocytes
Nunes, S. S., Miklas, J. W., Liu, J., Aschar-Sobbi, R., Xiao, Y., Zhang, B., Jiang, J., Massé, S., Gagliardi, M., Hsieh, A., et al. (2013) · Nature Methods · doi:10.1038/nmeth.2524 · Cited by 952 · see citing works
Self-citationEngineering Adolescence: Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes
Yang, X., Pabon, L., & Murry, C. E. (2014) · Circulation Research · doi:10.1161/circresaha.114.300558 · Cited by 939 · see citing works
Self-citationBurridge, P. W., Keller, G., Gold, J. D., & Wu, J. C. (2012) · Cell Stem Cell · doi:10.1016/j.stem.2011.12.013 · Cited by 670 · see citing works
Growth of engineered human myocardium with mechanical loading and vascular coculture
Tulloch, N. L., Muskheli, V., Razumova, M. V., Korte, F. S., Regnier, M., Hauch, K. D., Pabon, L., Reinecke, H., & Murry, C. E. (2011) · Circulation Research · doi:10.1161/circresaha.110.237206 · Cited by 666 · see citing works
Self-citationProangiogenic scaffolds as functional templates for cardiac tissue engineering
Madden, L. R., Mortisen, D. J., Sussman, E. M., Dupras, S. K., Fugate, J. A., Cuy, J. L., Hauch, K. D., Laflamme, M. A., Murry, C. E., & Ratner, B. D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1006442107 · Cited by 662 · see citing works
Self-citationTissue engineering of vascularized cardiac muscle from human embryonic stem cells
Caspi, O., Lesman, A., Basevitch, Y., Gepstein, A., Arbel, G., Habib, I. H. M., Gepstein, L., & Levenberg, S. (2007) · Circulation Research · doi:10.1161/01.res.0000257776.05673.ff · Cited by 558 · see citing works
Sharma, A., Burridge, P. W., McKeithan, W. L., Serrano, R., Shukla, P., Sayed, N., Churko, J. M., Kitani, T., Wu, H., Holmström, A., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aaf2584 · Cited by 404 · see citing works
Keung, W., Boheler, K. R., & Li, R. A. (2014) · Stem Cell Research & Therapy · doi:10.1186/scrt406 · Cited by 87 · see citing works
Titmarsh, D. M., Glass, N. R., Mills, R. J., Hidalgo, A., Wolvetang, E. J., Porrello, E. R., Hudson, J. E., & Cooper-White, J. J. (2016) · Scientific Reports · doi:10.1038/srep24637 · Cited by 59 · see citing works
- 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)
- PMC
- PMC3505759
- 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
- green
- www.ncbi.nlm.nih.gov
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review