Leveraging Factors Important During Cardiac Development to Disrupt Acquired Cardiovascular Disease
Cardiac development requires that multiple progenitor cell types undergo complex cell fate and morphological changes cooperatively to generate the four-chambered heart. Orchestration of this process is tightly regulated through the action of both transcription factors, and post-transcriptional regulators including microRNAs. Dysregulation of this process can lead to cardiac malformations that can result in congenital heart disease or lethality. Furthermore, decreased expression of key cardiac regulators are observed in acquired cardiovascular diseases including atherosclerosis and acute myocardial infarction, which are responsible for causing more fatalities per year than any other disease. Here we leverage the lessons we have learned from cardiac development and apply them to address acquired cardiovascular disease.
In the first study, we focus on post-transcriptional regulation of the vascular smooth muscle cells in the heart, which can contribute to plaque formation and disease progression in the context of atherosclerosis. We identified the microRNA miR-145 as sufficient to promote and maintain a differentiated, contractile smooth muscle phenotype in mutlipotent neural crest derived vascular smooth muscle cells. Further interrogation of miR-145 function indicates that miR-145 interacts with KLf4, a known activator of smooth muscle proliferation, in non-canonical van der waals interactions that target Klf4 for repression.
Next, we leverage key cardiac developmental transcription factors to address the loss of cardiomyocytes after acute myocardial infarction. We previously identified that forced expression of Gata4, Mef2c, and Tbx5 are sufficient to induce cardiac fibroblasts to acquire cardiomyocyte-like phenotypes, albeit at a low efficiency. Here we have generated a molecular roadmap of the transcriptional changes that occur throughout the process of fibroblast transdifferentiation to induced cardiomyocyte like cells (iCMs), in order to inform strategies to improve the efficiency iCM generation.
In these studies, we show that regulators of cardiac development have the potential to address acquired cardiovascular diseases.