Dedifferentiation and proliferation of mammalian cardiomyocytes

Yiqiang Zhang, Tao Sheng Li, Shuo Tsan Lee, Kolja A. Wawrowsky, Ke Cheng, Giselle Galang, Konstantinos Malliaras, M. Roselle Abraham, Charles Wang, Eduardo Marbán

Research output: Contribution to journalArticle

Abstract

Background: It has long been thought that mammalian cardiomyocytes are terminally-differentiated and unable to proliferate. However, myocytes in more primitive animals such as zebrafish are able to dedifferentiate and proliferate to regenerate amputated cardiac muscle. Methodology/Principal Findings: Here we test the hypothesis that mature mammalian cardiomyocytes retain substantial cellular plasticity, including the ability to dedifferentiate, proliferate, and acquire progenitor cell phenotypes. Two complementary methods were used: 1) cardiomyocyte purification from rat hearts, and 2) genetic fate mapping in cardiac explants from bi-transgenic mice. Cardiomyocytes isolated from rodent hearts were purified by multiple centrifugation and Percoll gradient separation steps, and the purity verified by immunostaining and RT-PCR. Within days in culture, purified cardiomyocytes lost their characteristic electrophysiological properties and striations, flattened and began to divide, as confirmed by proliferation markers and BrdU incorporation. Many dedifferentiated cardiomyocytes went on to express the stem cell antigen c-kit, and the early cardiac transcription factors GATA4 and Nkx2.5. Underlying these changes, inhibitory cell cycle molecules were suppressed in myocyte-derived cells (MDCs), while microRNAs known to orchestrate proliferation and pluripotency increased dramatically. Some, but not all, MDCs self-organized into spheres and re-differentiated into myocytes and endothelial cells in vitro. Cell fate tracking of cardiomyocytes from 4-OH-Tamoxifen-treated double-transgenic MerCreMer/ZEG mouse hearts revealed that green fluorescent protein (GFP) continues to be expressed in dedifferentiated cardiomyocytes, two-thirds of which were also c-kit+. Conclusions/Significance: Contradicting the prevailing view that they are terminally-differentiated, postnatal mammalian cardiomyocytes are instead capable of substantial plasticity. Dedifferentiation of myocytes facilitates proliferation and confers a degree of stemness, including the expression of c-kit and the capacity for multipotency. & copy; 2010 Zhang et al.

Original languageEnglish (US)
Article numbere12559
Pages (from-to)1-13
Number of pages13
JournalPLoS One
Volume5
Issue number9
DOIs
StatePublished - 2010

Fingerprint

Cardiac Myocytes
Plasticity
GATA4 Transcription Factor
myocytes
Muscle Cells
Centrifugation
Endothelial cells
Bromodeoxyuridine
Tamoxifen
Green Fluorescent Proteins
Stem cells
MicroRNAs
Purification
Muscle
Rats
Animals
heart
Cells
Antigens
Molecules

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Zhang, Y., Li, T. S., Lee, S. T., Wawrowsky, K. A., Cheng, K., Galang, G., ... Marbán, E. (2010). Dedifferentiation and proliferation of mammalian cardiomyocytes. PLoS One, 5(9), 1-13. [e12559]. https://doi.org/10.1371/journal.pone.0012559

Dedifferentiation and proliferation of mammalian cardiomyocytes. / Zhang, Yiqiang; Li, Tao Sheng; Lee, Shuo Tsan; Wawrowsky, Kolja A.; Cheng, Ke; Galang, Giselle; Malliaras, Konstantinos; Abraham, M. Roselle; Wang, Charles; Marbán, Eduardo.

In: PLoS One, Vol. 5, No. 9, e12559, 2010, p. 1-13.

Research output: Contribution to journalArticle

Zhang, Y, Li, TS, Lee, ST, Wawrowsky, KA, Cheng, K, Galang, G, Malliaras, K, Abraham, MR, Wang, C & Marbán, E 2010, 'Dedifferentiation and proliferation of mammalian cardiomyocytes', PLoS One, vol. 5, no. 9, e12559, pp. 1-13. https://doi.org/10.1371/journal.pone.0012559
Zhang Y, Li TS, Lee ST, Wawrowsky KA, Cheng K, Galang G et al. Dedifferentiation and proliferation of mammalian cardiomyocytes. PLoS One. 2010;5(9):1-13. e12559. https://doi.org/10.1371/journal.pone.0012559
Zhang, Yiqiang ; Li, Tao Sheng ; Lee, Shuo Tsan ; Wawrowsky, Kolja A. ; Cheng, Ke ; Galang, Giselle ; Malliaras, Konstantinos ; Abraham, M. Roselle ; Wang, Charles ; Marbán, Eduardo. / Dedifferentiation and proliferation of mammalian cardiomyocytes. In: PLoS One. 2010 ; Vol. 5, No. 9. pp. 1-13.
@article{db1ff2c22e7249459ea68ff6e97cd1c5,
title = "Dedifferentiation and proliferation of mammalian cardiomyocytes",
abstract = "Background: It has long been thought that mammalian cardiomyocytes are terminally-differentiated and unable to proliferate. However, myocytes in more primitive animals such as zebrafish are able to dedifferentiate and proliferate to regenerate amputated cardiac muscle. Methodology/Principal Findings: Here we test the hypothesis that mature mammalian cardiomyocytes retain substantial cellular plasticity, including the ability to dedifferentiate, proliferate, and acquire progenitor cell phenotypes. Two complementary methods were used: 1) cardiomyocyte purification from rat hearts, and 2) genetic fate mapping in cardiac explants from bi-transgenic mice. Cardiomyocytes isolated from rodent hearts were purified by multiple centrifugation and Percoll gradient separation steps, and the purity verified by immunostaining and RT-PCR. Within days in culture, purified cardiomyocytes lost their characteristic electrophysiological properties and striations, flattened and began to divide, as confirmed by proliferation markers and BrdU incorporation. Many dedifferentiated cardiomyocytes went on to express the stem cell antigen c-kit, and the early cardiac transcription factors GATA4 and Nkx2.5. Underlying these changes, inhibitory cell cycle molecules were suppressed in myocyte-derived cells (MDCs), while microRNAs known to orchestrate proliferation and pluripotency increased dramatically. Some, but not all, MDCs self-organized into spheres and re-differentiated into myocytes and endothelial cells in vitro. Cell fate tracking of cardiomyocytes from 4-OH-Tamoxifen-treated double-transgenic MerCreMer/ZEG mouse hearts revealed that green fluorescent protein (GFP) continues to be expressed in dedifferentiated cardiomyocytes, two-thirds of which were also c-kit+. Conclusions/Significance: Contradicting the prevailing view that they are terminally-differentiated, postnatal mammalian cardiomyocytes are instead capable of substantial plasticity. Dedifferentiation of myocytes facilitates proliferation and confers a degree of stemness, including the expression of c-kit and the capacity for multipotency. & copy; 2010 Zhang et al.",
author = "Yiqiang Zhang and Li, {Tao Sheng} and Lee, {Shuo Tsan} and Wawrowsky, {Kolja A.} and Ke Cheng and Giselle Galang and Konstantinos Malliaras and Abraham, {M. Roselle} and Charles Wang and Eduardo Marb{\'a}n",
year = "2010",
doi = "10.1371/journal.pone.0012559",
language = "English (US)",
volume = "5",
pages = "1--13",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "9",

}

TY - JOUR

T1 - Dedifferentiation and proliferation of mammalian cardiomyocytes

AU - Zhang, Yiqiang

AU - Li, Tao Sheng

AU - Lee, Shuo Tsan

AU - Wawrowsky, Kolja A.

AU - Cheng, Ke

AU - Galang, Giselle

AU - Malliaras, Konstantinos

AU - Abraham, M. Roselle

AU - Wang, Charles

AU - Marbán, Eduardo

PY - 2010

Y1 - 2010

N2 - Background: It has long been thought that mammalian cardiomyocytes are terminally-differentiated and unable to proliferate. However, myocytes in more primitive animals such as zebrafish are able to dedifferentiate and proliferate to regenerate amputated cardiac muscle. Methodology/Principal Findings: Here we test the hypothesis that mature mammalian cardiomyocytes retain substantial cellular plasticity, including the ability to dedifferentiate, proliferate, and acquire progenitor cell phenotypes. Two complementary methods were used: 1) cardiomyocyte purification from rat hearts, and 2) genetic fate mapping in cardiac explants from bi-transgenic mice. Cardiomyocytes isolated from rodent hearts were purified by multiple centrifugation and Percoll gradient separation steps, and the purity verified by immunostaining and RT-PCR. Within days in culture, purified cardiomyocytes lost their characteristic electrophysiological properties and striations, flattened and began to divide, as confirmed by proliferation markers and BrdU incorporation. Many dedifferentiated cardiomyocytes went on to express the stem cell antigen c-kit, and the early cardiac transcription factors GATA4 and Nkx2.5. Underlying these changes, inhibitory cell cycle molecules were suppressed in myocyte-derived cells (MDCs), while microRNAs known to orchestrate proliferation and pluripotency increased dramatically. Some, but not all, MDCs self-organized into spheres and re-differentiated into myocytes and endothelial cells in vitro. Cell fate tracking of cardiomyocytes from 4-OH-Tamoxifen-treated double-transgenic MerCreMer/ZEG mouse hearts revealed that green fluorescent protein (GFP) continues to be expressed in dedifferentiated cardiomyocytes, two-thirds of which were also c-kit+. Conclusions/Significance: Contradicting the prevailing view that they are terminally-differentiated, postnatal mammalian cardiomyocytes are instead capable of substantial plasticity. Dedifferentiation of myocytes facilitates proliferation and confers a degree of stemness, including the expression of c-kit and the capacity for multipotency. & copy; 2010 Zhang et al.

AB - Background: It has long been thought that mammalian cardiomyocytes are terminally-differentiated and unable to proliferate. However, myocytes in more primitive animals such as zebrafish are able to dedifferentiate and proliferate to regenerate amputated cardiac muscle. Methodology/Principal Findings: Here we test the hypothesis that mature mammalian cardiomyocytes retain substantial cellular plasticity, including the ability to dedifferentiate, proliferate, and acquire progenitor cell phenotypes. Two complementary methods were used: 1) cardiomyocyte purification from rat hearts, and 2) genetic fate mapping in cardiac explants from bi-transgenic mice. Cardiomyocytes isolated from rodent hearts were purified by multiple centrifugation and Percoll gradient separation steps, and the purity verified by immunostaining and RT-PCR. Within days in culture, purified cardiomyocytes lost their characteristic electrophysiological properties and striations, flattened and began to divide, as confirmed by proliferation markers and BrdU incorporation. Many dedifferentiated cardiomyocytes went on to express the stem cell antigen c-kit, and the early cardiac transcription factors GATA4 and Nkx2.5. Underlying these changes, inhibitory cell cycle molecules were suppressed in myocyte-derived cells (MDCs), while microRNAs known to orchestrate proliferation and pluripotency increased dramatically. Some, but not all, MDCs self-organized into spheres and re-differentiated into myocytes and endothelial cells in vitro. Cell fate tracking of cardiomyocytes from 4-OH-Tamoxifen-treated double-transgenic MerCreMer/ZEG mouse hearts revealed that green fluorescent protein (GFP) continues to be expressed in dedifferentiated cardiomyocytes, two-thirds of which were also c-kit+. Conclusions/Significance: Contradicting the prevailing view that they are terminally-differentiated, postnatal mammalian cardiomyocytes are instead capable of substantial plasticity. Dedifferentiation of myocytes facilitates proliferation and confers a degree of stemness, including the expression of c-kit and the capacity for multipotency. & copy; 2010 Zhang et al.

UR - http://www.scopus.com/inward/record.url?scp=77958614288&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77958614288&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0012559

DO - 10.1371/journal.pone.0012559

M3 - Article

C2 - 20838637

AN - SCOPUS:77958614288

VL - 5

SP - 1

EP - 13

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 9

M1 - e12559

ER -