Skip to main content

Tumor Suppressors RB1 and CDKN2a Cooperatively Regulate Cell-Cycle Progression and Differentiation During Cardiomyocyte Development and Repair.

Publication ,  Journal Article
Hatzistergos, KE; Williams, AR; Dykxhoorn, D; Bellio, MA; Yu, W; Hare, JM
Published in: Circ Res
April 12, 2019

RATIONALE: Although rare cardiomyogenesis is reported in the adult mammalian heart, whether this results from differentiation or proliferation of cardiomyogenic cells remains controversial. The tumor suppressor genes RB1 (retinoblastoma) and CDKN2a (cyclin-dependent kinase inhibitor 2a) are critical cell-cycle regulators, but their roles in human cardiomyogenesis remains unclear. OBJECTIVE: We hypothesized that developmental activation of RB1 and CDKN2a cooperatively cause permanent cell-cycle withdrawal of human cardiac precursors (CPCs) driving terminal differentiation into mature cardiomyocytes, and that dual inactivation of these tumor suppressor genes promotes myocyte cell-cycle reentry. METHODS AND RESULTS: Directed differentiation of human pluripotent stem cells (hPSCs) into cardiomyocytes revealed that RB1 and CDKN2a are upregulated at the onset of cardiac precursor specification, simultaneously with GATA4 (GATA-binding protein 4) homeobox genes PBX1 (pre-B-cell leukemia transcription factor 1) and MEIS1 (myeloid ecotropic viral integration site 1 homolog), and remain so until terminal cardiomyocyte differentiation. In both GATA4+ hPSC cardiac precursors and postmitotic hPSC-cardiomyocytes, RB1 is hyperphosphorylated and inactivated. Transient, stage-specific, depletion of RB1 during hPSC differentiation enhances cardiomyogenesis at the cardiac precursors stage, but not in terminally differentiated hPSC-cardiomyocytes, by transiently upregulating GATA4 expression through a cell-cycle regulatory pathway involving CDKN2a. Importantly, cytokinesis in postmitotic hPSC-cardiomyocytes can be induced with transient, dual RB1, and CDKN2a silencing. The relevance of this pathway in vivo was suggested by findings in a porcine model of cardiac cell therapy post-MI, whereby dual RB1 and CDKN2a inactivation in adult GATA4+ cells correlates with the degree of scar size reduction and endogenous cardiomyocyte mitosis, particularly in response to combined transendocardial injection of adult human hMSCs (bone marrow-derived mesenchymal stromal cells) and cKit+ cardiac cells. CONCLUSIONS: Together these findings reveal an important and coordinated role for RB1 and CDKN2a in regulating cell-cycle progression and differentiation during human cardiomyogenesis. Moreover, transient, dual inactivation of RB1 and CDKN2a in endogenous adult GATA4+ cells and cardiomyocytes mediates, at least in part, the beneficial effects of cell-based therapy in a post-MI large mammalian model, a finding with potential clinical implications.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

April 12, 2019

Volume

124

Issue

8

Start / End Page

1184 / 1197

Location

United States

Related Subject Headings

  • Up-Regulation
  • Swine
  • Pre-B-Cell Leukemia Transcription Factor 1
  • Pluripotent Stem Cells
  • Myocytes, Cardiac
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Induced Pluripotent Stem Cells
  • Humans
  • Genes, p16
  • Genes, Retinoblastoma
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Hatzistergos, K. E., Williams, A. R., Dykxhoorn, D., Bellio, M. A., Yu, W., & Hare, J. M. (2019). Tumor Suppressors RB1 and CDKN2a Cooperatively Regulate Cell-Cycle Progression and Differentiation During Cardiomyocyte Development and Repair. Circ Res, 124(8), 1184–1197. https://doi.org/10.1161/CIRCRESAHA.118.314063
Hatzistergos, Konstantinos E., Adam R. Williams, Derek Dykxhoorn, Michael A. Bellio, Wendou Yu, and Joshua M. Hare. “Tumor Suppressors RB1 and CDKN2a Cooperatively Regulate Cell-Cycle Progression and Differentiation During Cardiomyocyte Development and Repair.Circ Res 124, no. 8 (April 12, 2019): 1184–97. https://doi.org/10.1161/CIRCRESAHA.118.314063.
Hatzistergos KE, Williams AR, Dykxhoorn D, Bellio MA, Yu W, Hare JM. Tumor Suppressors RB1 and CDKN2a Cooperatively Regulate Cell-Cycle Progression and Differentiation During Cardiomyocyte Development and Repair. Circ Res. 2019 Apr 12;124(8):1184–97.
Hatzistergos, Konstantinos E., et al. “Tumor Suppressors RB1 and CDKN2a Cooperatively Regulate Cell-Cycle Progression and Differentiation During Cardiomyocyte Development and Repair.Circ Res, vol. 124, no. 8, Apr. 2019, pp. 1184–97. Pubmed, doi:10.1161/CIRCRESAHA.118.314063.
Hatzistergos KE, Williams AR, Dykxhoorn D, Bellio MA, Yu W, Hare JM. Tumor Suppressors RB1 and CDKN2a Cooperatively Regulate Cell-Cycle Progression and Differentiation During Cardiomyocyte Development and Repair. Circ Res. 2019 Apr 12;124(8):1184–1197.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

April 12, 2019

Volume

124

Issue

8

Start / End Page

1184 / 1197

Location

United States

Related Subject Headings

  • Up-Regulation
  • Swine
  • Pre-B-Cell Leukemia Transcription Factor 1
  • Pluripotent Stem Cells
  • Myocytes, Cardiac
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Induced Pluripotent Stem Cells
  • Humans
  • Genes, p16
  • Genes, Retinoblastoma