Reprogramming Cardiac Cell Fates: New Paradigm for Heart Repair and Regeneration.
A fundamental, but unsolved problem in heart diseases is irreversible loss of cardiomyocytes that is replaced by fibrotic scar in response to injury. Therefore, to convert cardiac fibroblasts, the most abundant cell type in the heart, into cardiomyocytes after injury is a particularly attractive heart repair strategy. Over the last four years, we have taken three fundamental steps toward this goal: 1) in vitro reprogramming of adult mouse fibroblasts into beating cardiomyocytes by forced expression of four transcription factors, 2) developing in vivo reprogramming strategy targeting activated cardiac fibroblasts after myocardial infarction, which improved heart function and reduced scar formation, and 3) identifying the optimal combination of factors that is necessary and sufficient to induce a contractile phenotype in adult human fibroblasts.
There are three major types of cardiomyocytes in the heart as defined by anatomical location and unique electrical properties: atrial, ventricular, and pacemaker. Highly coordinated activity of all three cardiac subtypes is required for effective blood pumping. Thus, significant loss or dysfunction of individual cardiac subtypes can lead to specific forms of potentially life-threatening heart disease depending upon the identity of the affected cell type. However, all current heart repair strategies have been focused on regeneration of heart muscle without subtype specification. The inability to specify subtype of cardiomyocytes has been a main barrier to clinical application of newly generated muscle cells derived from either differentiation or reprogramming method. Therefore, an ideal heart repair strategy would be able to selectively generate the right type of heart cells in the right place of the heart depending on the type of heart disease. Thus, our research goals are 1) to develop an entirely new heart repair strategy targeting specific heart disease by generation of individual subtypes of cardiomyocytes including atrial, ventricular, and pacemaker cardiomyocytes and 2) to understand the mechanistic basis of cardiac cell fate specification during direct cardiac reprogramming and pluripotent stem cell differentiation.