Nestin- and Nestin-Ventricular Cardiomyocytes Reenter the Cell Cycle In Vitro but Are Reciprocally Regulated in the Partial Apex-Resected 7-Day Neonatal Rat Heart.

The 1-day-old neonatal rat heart contains two subpopulations of ventricular cardiomyocytes (NNVMs) that reenter the cell cycle in vitro and in vivo distinguished by the absence or de novo expression of the intermediate filament protein nestin. Furthermore, de novo nestin expression in NNVMs directly facilitated cell cycle reentry and elicited a morphological migratory phenotype. Previous studies have reported that ventricular cardiomyocytes failed to reenter the cell cycle following damage to the 7-day-old rodent heart. The present study tested the hypothesis that cell cycle reentry of one or both of the NNVM subpopulations of 7-day-old neonatal rat pups was compromised in vitro and/or in vivo following cardiac damage. Three-day treatment of 7-day-old NNVMs with the protein kinase C activator phorbol 12,13-dibutyrate and the serine/threonine p38α/β MAPK kinase inhibitor SB203580 facilitated cell cycle reentry into the S phase and G-M phase of the cell cycle. Two distinct subpopulations of 7-day NNVMs reentered the cell cycle, and the predominant subpopulation was distinguished by de novo nestin expression. Three days following the sham-operation of 7-day-old neonatal rat hearts, cell cycle reentry was detected exclusively in NNVMs lacking nestin expression. Partial apex resection of 7-day-old neonatal rat hearts led to the de novo appearance of nestin-NNVMs preferentially bordering the damaged region and a subpopulation reentered the S-phase and G-M phase of the cell cycle in the absence of p38α/β MAPK inhibition. By contrast, cell cycle reentry of nestin-NNVMs identified adjacent to the apex-resected region was significantly reduced. These data highlight the disparate in vivo regulation of the two subpopulations of NNVMs following damaged to the 7-day-old neonatal rat heart and reaffirm the premise that targeting the subpopulation of nestin-ventricular cardiomyocytes identified in the ischemically damaged adult mammalian heart represents a plausible first step to initiate cell cycle reentry.