Reprogramming Fibroblasts into Cardiomyocyte-like Cells in the Aging Heart
2013 new Scholar Award in aging
The incidence of myocardial infarction (MI), also known as heart attack, significantly increases with age, and is the leading cause of morbidity and mortality among the population aged 65 years and older. The underlying pathology is typically loss of cardiomyocytes that leads to heart failure. Recently, we showed that in a murine model of acute MI, delivery of three transcription factors, Gata4, Mef2c and Tbx5 (GMT) converted cardiac fibroblasts (CFs) into functional induced cardiomyocytes (iCMs). These iCMs integrated electrically and mechanically with surrounding myocardium, resulting in a reduction in scar size and an improvement in heart function. Our findings point to a novel strategy for cardiac regeneration in an injured heart. However, the applicability of CF reprogramming is currently limited to the young MI hearts in which it has been attempted. As MI is more prevalent and devastating in the aging population, it is important to determine if direct cardiac reprogramming can be a viable therapeutic approach for older patients with MI. Therefore, we will further develop our CF reprogramming models in older mice and test whether reprogramming can occur with aged fibroblasts. We will also study how aging regulates CF reprogramming by comparing the chromatin structure dynamics of GMT-transduced old and young CFs. Based on our preliminary studies, we hypothesize that the aged CFs can be reprogrammed into iCMs in vivo in a murine MI model but with a lower efficiency, which may be due to a less accessible chromatin structure. Our ultimate goal is to use the knowledge learned from our proposed experiments to improve the efficiency and clinical applicability of direct cardiac reprogramming on MI patients who are prevalent in the aging population.