Intercellular and extracellular adhesion signals control cardiac myocyte structural and functional remodeling

Abstract

Heart failure is a major clinical and public health problem worldwide. During development and in many forms of progressive heart failure, a mechanical substrate may be the causative mediator whereby changes in myocyte shape are largely responsible for cardiac remodeling. The long-term preservation or enhancement of cardiac function depends on structural adaptation. The extracellular matrix (ECM) of the heart provides biochemical and mechanical cues, involved in morphogenesis and pathogenesis. What remains unclear is how these mechanical cues influence cardiomyocyte maturation during both development and disease progression. The central objective of this thesis is to examine the effect of cell-cell (N-cadherin) mediated mechanical forces and the combined effect of cell-matrix biochemical and mechanical cues directing myocyte structure and function.Cardiac myocytes were cultured on either N-cadherin or matrix ligands conjugated to inert polyacrylamide gels of defined elastic modulus. Myocyte shape, cytoskeletal architecture, mechanical properties and force generating profiles were analyzed. Our results indicate a remarkable structural and functional adaptation to perceived forces that are mediated by N-cadherin and matrix adhesions. Engineering cardiac myocytes using micropatterned geometries were used to map the distribution of mechnosensory proteins associated with the N-cadherin complex, demonstrating that -catenin is a key adaptor protein.Relating the results of in vitro studies in which cells are cultured on inert synthetic materials to the function of cells within biologically relevant gels is not obvious. Hyaluronan, a glycosaminoglycan expressed during cardiac development and disease, was used to engineer a physiologically relevant cardiac biosynthetic gel. Remarkably, myocytes cultured on much lower stiffnesses than normal cardiac tissue exhibited a developmental hypertrophic response with well assembled sarcomeric architecture, compared to inert gels inducing atrophy. Furthermore, hyaluronan receptors (CD44 and RHAMM) can modulate integrin-mediated signaling, effectively reprogramming the myocyte structure-function response. This mechanism and gain of function response was previously unknown in field of cardiac biology.The results from this thesis form the basis and rationale for engineering a new class of injectable hydrogels that can be used as part of a surgical and therapeutic strategy to reverse the remodeling process of the diseased heart.%%%%Ph.D., Biomedical Engineering – Drexel University, 2012