The ability to produce new myocytes within the heart would revolutionize our ability to treat cardiovascular disease, and new strategies for generating new cardiac muscle cells (cardiomyocytes) after injury, such as myocardial infarction (MI), are needed. Adult mammalian cardiomyocytes (CM) are generally considered to be post-mitotic, hence previous nongenetic strategies to stimulate resident CM proliferation have to date been insufficient to overcome CM loss with injury. However, recent reports demonstrate that adult differentiated CMs in humans and mice have the ability to proliferate, albeit at low frequency, suggesting that these rare events could be harnessed at a larger scale if the underlying mechanisms were fully understood. Developmental studies show that the transcription factor Tbx20 promotes CM proliferation in the fetal and neonatal heart. Tbx20 overexpression (Tbx20OE) in adult CMs induces fetal-like characteristics, including proliferation, smaller size, mononucleation, and fetal contractile protein expression. We hypothesize that induction of adult CM proliferation via a Tbx20-dependent pathway requires both partial dedifferentiation, mediated by increased BMP signaling, and repression of cell cycle inhibitors, including Btg2.
The Aims are: 1) Determine if transient or exogenous Tbx20 expression is sufficient to promote adult CM proliferation and repair in vivo. 2) Determine if BMP signaling promotes CM dedifferentiation necessary for induction of adult CM proliferation in vivo. 3) Determine if loss of cell cycle inhibitors Btg1/2 promotes CM proliferation and repair after injury. The ability to induce resident adult mammalian CMs to proliferate by physiologic reversion to a fetal-like state would be an important advance in efforts to generate new myocardium after cardiac injury.
Cardiovascular disease is the leading cause of death in the world, and treatments are limited by the innate inability of adult cardiac muscle cells to proliferate or regenerate after injury. The potential of adult cardiac muscle cells to revert to a fetal-like state with increased proliferation and functional improvement after injury will be examined. Administration of virally-expressed factors that promote fetal-like heart muscle characteristics will be tested as a possible new therapeutic approach after myocardial infarction.
| Wu, Bingruo; Wang, Yidong; Xiao, Feng et al. (2017) Developmental Mechanisms of Aortic Valve Malformation and Disease. Annu Rev Physiol 79:21-41 |
| Yutzey, Katherine E (2017) Cardiomyocyte Proliferation: Teaching an Old Dogma New Tricks. Circ Res 120:627-629 |
| Wirrig, Elaine E; Yutzey, Katherine E (2014) Conserved transcriptional regulatory mechanisms in aortic valve development and disease. Arterioscler Thromb Vasc Biol 34:737-41 |
