Cell cycle regulation in mouse heart during embryonic and postnatal stages

Abstract

The regulation of cardiomyocyte proliferation is important for heart development and function. Proliferation levels of mouse cardiomyocytes are high during early embryogenesis and start to decrease at midgestation. Many cardiomyocytes undergo mitosis without cytokinesis, resulting in binucleated cardiomyocytes during early postnatal stages, following which the cell cycle arrests irreversibly. It remains unknown how the proliferation pattern is regulated, and how the irreversible cell cycle arrest occurs. To clarify the mechanisms, fundamental information about cell cycle regulators in cardiomyocytes and cell cycle patterns during embryonic and postnatal stages is necessary. Here, we show that the expression, complex formation, and activity of main cyclins and cyclindependent kinases (CDKs) changed in a synchronous manner during embryonic and postnatal stages. These levels decreased from midgestation to birth, and then showed one wave in which the peak was around postnatal day 5. Detailed analysis of the complexes suggested that CDK activities were inhibited before the protein levels decreased. Analysis of DNA content distribution patterns in mono-and binucleated cardiomyocytes after birth revealed changes in cell cycle distribution patterns and the transition from mono-to binucleated cells. These analyses indicated that the wave of cell cycle regulator expression or activities during postnatal stages mainly produced binucleated cells from mononucleated cells. The data obtained should provide a basis for the analysis of cell cycle regulation in cardiomyocytes during embryonic and postnatal stages.

Repression of Cyclin D1 Expression Is Necessary for the Maintenance of Cell Cycle Exit in Adult Mammalian Cardiomyocytes

“…Simultaneously, almost all CMs exit the cell cycle, and the state is strictly maintained. The nuclear DNA content of almost all CMs is 2C (6,9), showing the cell cycle exit from G 1 -phase.…”

“…The wave mainly produces binucleated cells from mononucleated cells. Eighty to ninety percent of CMs become binucleated cells (7,9). Then all expression and activation levels of main cyclin-CDK complexes become extremely low or undetectable after P14, and the levels are maintained for life.…”

Postnatal telomere dysfunction induces cardiomyocyte cell-cycle arrest through p21 activation

“…During embryonic development (Soonpaa et al, 1994;Drenckhahn et al, 2008) and on postnatal day 1 (P1; Porrello et al, 2011), CMs in the mouse heart are able to proliferate, showing significant regeneration capacity. However, during the first two postnatal weeks, most mouse CMs become binucleated and withdraw from the cell cycle (Soonpaa et al, 1996;Ikenishi et al, 2012). As a consequence, the capacity for complete cardiac regeneration after injury is lost around P7 (Porrello et al, 2011(Porrello et al, , 2013.…”

Development of multiplex PCR systems for expression profiling of human cardiomyocytes induced to proliferate by lentivirus transduction of upcyte genes

“…To better understand molecular processes leading to myocardial diseases and to validate new cardiovascular drugs, relevant in vitro systems of human atrial and ventricular cardiomyocytes are required. However, use of primary human cardiomyocyte cultures is restricted due to the postmitotic state of this cell type [2][3][4][5]. Attempts for specific cardiomyocyte differentiation from pluripotent stem cells are still hampered by the fetal phenotype of obtained heart muscle cells [6,7].…”