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Visualization of Cell Cycle Variations and Determination of Nucleation in Postnatal Cardiomyocytes
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Two inhibitory systems and CKIs regulate cell cycle exit of mammalian cardiomyocytes after birth

Shoji Tane1, Hitomi Okayama1, Aiko Ikenishi1

  • 1School of Life Sciences, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan.

Biochemical and Biophysical Research Communications
|September 13, 2015
PubMed

Insights

Postnatal cardiomyocytes exit the cell cycle due to inhibitory systems and CDK inhibitors (CKIs). Loss of p21(Cip1) allows cell cycle entry and endoreplication, revealing its role in preventing cardiomyocyte proliferation.

Area of Science:

  • Cardiovascular Biology
  • Cell Cycle Regulation
  • Molecular Cardiology

Background:

  • Mammalian cardiomyocytes proliferate during embryonic development but exit the cell cycle postnatally.
  • Two inhibitory systems (G1-phase and M-phase) maintain this cell cycle exit in adult cardiomyocytes.
  • CDK inhibitors (CKIs) p21(Cip1) and p27(Kip1) are known to regulate cell cycle exit in some postnatal cardiomyocytes.

Purpose of the Study:

  • To investigate the role of the G1-phase and M-phase inhibitory systems in postnatal cardiomyocyte cell cycle exit.
  • To determine if p21(Cip1) and p27(Kip1) also inhibit cardiomyocyte entry into M-phase.
  • To elucidate the mechanisms maintaining cardiomyocyte cell cycle arrest after birth.

Main Methods:

  • Induction of cyclin D1 expression to promote cell cycle entry in postnatal cardiomyocytes.
  • Analysis of cardiomyocyte cell cycle progression and M-phase entry.
  • Assessment of cell cycle progression and ploidy in p21(Cip1) knockout mice.

Main Results:

  • Over 40% of postnatal cardiomyocytes entered an additional cell cycle upon cyclin D1 induction, but M-phase entry was largely inhibited.
  • Significant cell cycle progression and endoreplication were observed in p21(Cip1) knockout mice at 4 weeks.
  • Tri- and tetranucleated cardiomyocytes increased significantly in p21(Cip1) knockout mice, indicating failed cytokinesis.

Conclusions:

  • The G1-phase inhibitory system and CKIs p21(Cip1)/p27(Kip1) inhibit entry into an additional cell cycle in postnatal cardiomyocytes.
  • The M-phase inhibitory system and p21(Cip1) specifically inhibit M-phase entry in cardiomyocytes that have initiated cell cycle progression.
  • These findings highlight key regulators of cardiomyocyte cell cycle exit and potential targets for cardiac regeneration research.
Keywords:
CDK inhibitorCDK1CardiomyocyteCell cycle exitCyclin D1Karyokinesis

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