Cardiac Regeneration, Stem Cells Research

Members of the Cardiac Regeneration & Stem Cells theme are developing gene therapies to treat ischemic heart disease and in particular, ischemic heart failure, which is the leading cause of mortality in the Western world. The goal is to use gene therapy to induce cell cycle in cardiomyocytes, transdifferentiation of cardiac fibroblasts into functional cardiomyocytes, and/or increase vascularization of the infarct myocardium. New therapies have been advanced to clinical trials (NCT06831825) for advanced heart failure by inhibiting HIPPO signaling and increasing vascularization by delivering proangiogenic factor VEGFA. Preclinical models in rats, pigs, and in human heart slices are progressing well and provide further opportunities for the development of new therapies.

Members of the Cardiac Regeneration & Stem Cells theme are involved in research aimed at improving heart function after different types of injury and in particular the devastating loss of heart muscle after myocardial infarction. One current approach is to investigate gene pathways, many of which are important in heart development, that enhance the ability of cardiac muscle to respond to injury. Recent exciting findings, which are currently in clinical trail, have shown that manipulations of specific genetic pathways, such as the HIPPO pathway, enhance heart repair. Current investigations in this area include uncovering the molecular mechanisms underlying improved heart repair in order to develop novel therapies.

Another exciting approach involves in vivo reprogramming of cardiac fibroblasts into cardiac muscle as a way to enhance heart function after ischemic injury. This novel method was inspired by the observation by Yamanaka that fibroblasts can be reprogrammed to pluripotent cells in cultured cells. Important recent work has shown that providing a cocktail of factors to cardiac fibroblasts results in conversion of those fibroblasts directly into cardiac muscle. Current efforts are directed at improving the efficiency of in vivo reprogramming with the goal of using this approach in therapy, recognizing that use of this strategy in human cells will likely be more challenging than in rodent and other non-human strains. The combination of angiogenic treatment of scar with this strategy appears to be enhance the efficacy of such regenerative approaches.

Furthermore, CVRI researchers have developed a novel technology to culture human heart slices for extended periods of time. This technology allows researchers to study the structural and functional properties of heart tissue in a controlled laboratory setting. Most importantly this  technology is currently in use for drug discovery and development. By testing the effects of different compounds on heart tissue slices, researchers can identify potential drug candidates and assess their safety and efficacy. This approach can help accelerate the drug development process and reduce the reliance on animal models.

James F Martin, M.D. Ph.D. - Inducing the cardiac regenerative niche and human gene therapy clinical trials

Tamer Mohamed, Ph.D. - Cardiomyocyte cell cycle, and Human heart slice culture

Riham R. E. Aboleisa, Ph.D. Cardiomyocyte cell cycle regulation

Ravi Birla, Ph.D. – Congenital heart disease repair, organoids

Katarzyna Cieslik, Ph.D. - Cardiac mesenchymal progenitors

Thomas Cooper, M.D. - Alternative splicing in cardiac development and disease

Peggy Goodell, M.D. - Hematopoietic stem cells, epigenetic modifications

Todd K Rosengart, M.D. - Direct reprogramming and angiogenesis