California's Stem Cell Agency

Key abbreviations: CDCs: cardiosphere-derived cells MI: myocardial infarction The present award tests the hypothesis that CDCs promote regrowth of normal mammalian heart tissue through induction of adult cardiomyocyte cell cycle re-entry and proliferation (as occurs naturally in zebrafish and neonatal mice). Such a mechanism, if established, would challenge the dogma that terminally-differentiated adult cardiomyocytes cannot re-enter the cell cycle. We have employed an inducible cardiomyocyte-specific fate-mapping approach (to specifically mark resident myocytes and their progeny), coupled with novel methods of myocyte purification and rigorous quantification. We have also developed assays that enable us to exclude potential technical confounding factors. The use of bitransgenic mice is essential for our experimental design (as it enables fate mapping of resident myocytes in a mammalian model), while the use of mouse CDCs in our in vivo experiments (as opposed to human CDCs) enables us to avoid immunosuppression and its complications. To date, mouse, rat and pig models have proven to be reliable in predicting clinical effects of CDC therapy in humans, and results with human and mouse CDCs in comparable models (e.g., SCID mice for human CDCs versus wild-type mice for mouse CDCs) have not revealed any major mechanistic divergence. Our results demonstrate that induction of cardiomyocyte proliferation represents a major, previously-unrecognized mechanism of cardiac regeneration in response to cell therapy. One full-length publication describing these findings has appeared (K. Malliaras et al., EMBO Mol Med, 2013, 5:191-209), and another paper has been submitted. The work has already begun to open up novel mechanistic insights which will enable us to improve the efficacy of stem cell-based treatments and bolster cardiomyocyte repopulation of infarcted myocardium.