Repair of myocardial tissue using mechanisms analogous to those taking place during embryonic development is a promising avenue for treatment of cardiac diseases. To realize the promise of regenerative cardiac medicine, we need to understand the dynamic and mutually interdependent mechanical relationship between cells and the extracellular matrix (ECM) microenvironment, and their reciprocal impact on cell differentiation and tissue morphogenesis. The overall objective of this project is to establish how interactions between ECM structure and cell behavior modulate cardiomyocyte differentiation on the cellular level, and contribute to myocardium formation on the tissue level. Our central hypothesis is that by exerting forces on the ECM microenvironment, differentiating cardiomyocytes can actively remodel the ECM structure and change its micromechanical properties. These changes, in turn, enhance CMC differentiation -- constituting a feedback regulation loop. The proposed research would establish the principles of the cardiomyocite - ECM feedback regulation, both in avian embryos and in cultures of human iPSC-derived cardiomyocyte cultures, in sufficient detail to enable practical applications. Accordingly, our specific aims are: 1. Identify how physical properties of the ECM microenvironment affect CMC differentiation and survival. 2. Identify the interplay between CMC behavior, reorganization of ECM structure and micromechanical properties of the differentiating myocardium. The data generated during the envisioned research will fill a knowledge gap regarding micromechanical feedback regulation during cardiomyocyte differentiation, and clarify the mechanism of a prevalent, yet poorly understood, mode of collective cell behavior. Advanced optical timelapse microscopy and image analysis methods, in vivo and in vitro, as well as the resulting computational tools developed here, will enable future translational studies exploring disease mechanisms or automated high throughput exploration of drug effects on cardiomyocyte contractility, differentiation and survival.
|Effective start/end date||07/01/2016 → 06/30/2018|