Mechanisms to enhance cardiac regeneration

The adult heart has very limited ability to regenerate. Therefore, cell loss due to disease, such as a heart attack, is essentially irreversible and may lead to heart failure. Increasing cardiomyocyte number in damaged hearts has potential for substantial clinical benefit. Three approaches to increasing cardiomyocyte number were tested: cellular transplantation of bone marrow-derived stem cells, an inducible system for adult cardiomyocyte cell cycle re-entry, and modulation of cardiomyocyte cell cycle regulatory proteins. Firstly, hematopoietic stem cells were tested as a donor cell source for engraftment in adult mouse hearts. Results using reporter transgenes showed engrafted hematopoietic stem cells do not acquire a cardiac phenotype, raising a cautionary note for clinical studies of infarct repair. Secondly, a regulatable system for inducing cardiomyocyte cell cycle activity was generated. Results using transgenic mice showed induced expression of simian virus large T antigen (T-Ag) in adult cardiomyocytes sufficiently reactivated cell cycle. This may prove important in regulating adult cardiomyocyte cell cycle and in improving cellular transplant outcome. The third approach studied two cell cycle regulatory genes. First, transgenic mice expressing a mutant A subunit of protein phosphatase 2A (PP2A) were examined. These mice had increased heart weights at birth suggesting transgene expression might drive cardiac growth. Analyses revealed a ∼4,000% increase in cardiomyocyte DNA synthesis in PP2A mice. Second, the molecular pathway of p193, a novel cardiomyocyte T-Ag binding partner was studied. Recently, transgenic mice expressing mutant p193 showed increased DNA synthesis in diseased hearts. To elucidate p193 function, two anti-p193 antibodies were generated. Results showed p193 associates with the novel protein Parc and occasionally with tumor suppressor p53. Mutant p193 expression rendered cells resistant to apoptosis induced by DNA damage or proteasome inhibition. These data are consistent with a p193 role in ubiquitin-mediated apoptosis. These findings provide insight in the cardioprotection in mutant p193-expressing mice and the role of the ubiquitin/proteasome pathway in apoptosis regulation. These three approaches to increasing cardiomyocyte number will further our understanding of the molecular regulation of the cardiomyocyte cell cycle and differentiation, and may provide new mechanisms to induce therapeutic cardiomyocyte regrowth/regeneration.