Although the field of cardiac stem cell therapy has significantly advanced over the past years, the premise of regenerating or replacing diseased human myocardium with functional tissue remains unsatisfied. The overall objective of our research is to promote myocardial stem cell therapy through nano-/micro-environmental engineering the intramyocardial stem cell niche for endogenous cardiac stem cells to reactivate, proliferate, differentiate and repopulate the diseased myocardium. Using a cardiac specific inducible Cre-Lox transgenic mouse strain, we have found that an endogenous cardiac stem cell pool may contribute to ~15% of new cardiomyocytes in the peri-infarcted area, saturated as early as within the first 2 weeks after infarction. Accordingly, we focus on (1) animal models to identify the source of this cardiac stem cell pool, and (2) methods to engineer the cardiac nano-/micro-environments for augmenting the regenerative signaling for spontaneous repair. Thus, we employ a team approach which brings together people from a broad variety of backgrounds, including stem biology, engineering and medicine . This combination has allowed us to work together and interact in a way traditionally not available at an individual laboratory or program.