Associate Professor Medicine, Cardiology
Mount Sinai School of Medicine
Human Derived 3-D Engineered Cardiac Tissue for Clinically Translatable in vitro Screening Applications
The creation of human cardiac muscle in the tissue culture laboratory could significantly enhance the development of new treatments for heart disease; such 3-D models with controlled biological complexity and long-term viability, would allow for in vitro monitoring of contractile function and high-throughput screening of novel therapies which are not possible with the use of traditional cell culture methods. We have been successful in the creation of engineered cardiac tissues (ECT) using neonatal rat derived cardiomyocytes. Although such engineered tissues can provide powerful tools for in vitro investigation, it is essential that efforts be initiated to focus on human-derived cell sources to facilitate bench-to-bedside translation of results.
For this purpose we have designed two specific aims: 1) To create functional 3D human engineered cardiac tissues (3D-hECT) containing cardiomyocytes derived from human embryonic stem cells; optimize the electrical, mechanical, and biochemical tissue culture environment to yield ECT with molecular and cellular characteristics mimicking adult myocardium; and explore their potential as therapeutic and toxicology screening tools. 2) To create individualized ECT with cardiomyocytes derived from human induced pluripotent stem cells, and assess their capacity to reconstitute key aspects of patient-specific cardiac phenotypes.
This proposal involves research activities that are largely developmental and exploratory in nature, and are therefore considered high-risk ideas. In particular, human cardiomyocyte populated ECT have never been published, and the ability to induce iPSC reprogramming and cardiomyocyte differentiation in a physiologic 3D scaffold environment remains untested. In addition, the extent to which such derived tissues will reproduce essential characteristics of the natural donor tissue remains a critical unanswered question. Although some technical challenges are substantial, we are confident that the assembled multi-disciplinary research team has the complementary expertise required to make significant progress toward achieving the aims of this proposal.