Laboratory for Cardiac Regeneration | Baylor College of …

Researchers in the Laboratory for Cardiac Regeneration in the Michael E. DeBakey Department of Surgery at Baylor College of Medicine arestudying whether cellular reprogramming can be applied to improve cardiac infarct remodelingand function by testing the serial hypotheses that: a) inadequate up-regulation of requisitereprogramming genes limits cell transdifferentiation efficiency, which can be optimized beyondcurrent thresholds via the comprehensive application of genomic activation strategies, b) thatthe density of (contractile) iCMs in infarct zones as well as indirect or paracrine (i.e., antifibrotic)mechanisms play critical roles in GMT/VEGF mediated infarct remodeling, and c) thatcardiac fibroblasts can be made susceptible to reprogramming in a clinically relevant fashion.

The labemployscutting-edge molecular strategies and pre-clinical animal models to executethese aims.

Congestive heart failure typically occurring as a result of myocardial infarction remains theleading cause of mortality from heart disease. Cardiac stem cell therapy has offered promise inanimal and clinical studies, but remains inherently constrained by the logistical challenges ofdelivering and integrating exogenous cells into a host myocardium. The recent discovery thatinduced cardiomyocytes (iCMs) could be generated directly from somatic cells offers theexciting possibility of bypassing stem cell staging and, perhaps more importantly, convertingscar fibroblasts in situ into iCMs, obviating entirely the challenges of cell implantation into ahost myocardium.

Dr. Todd K. Rosengart and his teamhave recently demonstrated that the administration ofa cardiac transcription factor cocktail (e.g., GATA4, MEF2c and TBX5) results in as muchas a 50 percent increase in ventricular function, reduced fibrosis, and increased iCM populations insmall animal myocardial infarction models.

Intriguingly, also demonstrating that reductions ininfarct size appear to far exceed the extent of scar re-population with iCMs, and that GMT alsoappears to reduce the population of (scar-producing) myofibroblasts as well as the expressionof key scar remodeling cytokines. These data, and our observation that GMT efficacy isenhanced by the angiogenic pre-treatment of myocardial scar with vascular endothelial growthfactor (VEGF), suggest the existence of unexplored and non-optimized underlying mechanisms.

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Laboratory for Cardiac Regeneration | Baylor College of ...