Ph.D. Thesis Defense - Intercellular and Extracellular Adhesion Signals Control Cardiac Myocyte Structural and Functional Remodeling: Cadherin and Hyaluronan Receptor Mediated Mechanosensing
Date: May 24, 2012
Time: 1:00 PM
Location: Bossone Research Enterprise Center, Room: 709
Speaker(s):
Anant Chopra
Advisors: Adrian Shieh, Ph.D., J. Yasha Kresh, Ph.D., and Paul Janmey, Ph.D.
Details:
Heart failure is a major clinical and public health problem worldwide. During development and in many forms of progressive heart failure (e.g., ischemic, hypertrophic, and dilated cardiomyopathy), a mechanical substrate may be the causative mediator whereby changes in myocyte shape are largely responsible for adaptive as well as maladaptive cardiac remodeling. The long-term preservation or enhancement of cardiac function depends on structural adaptation. The extracellular matrix (ECM) of the heart is a complex meshwork providing biochemical as well as mechanical cues (i.e. ECM stiffness, cell shape) is involved in cardiac 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 as well as the combined effect of cell-matrix biochemical and mechanical cues direct 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 and mechanical properties in addition to force generating profiles were analyzed using gel substrates of controlled elasticity. Our results indicate that myocytes show a remarkable structural and functional adaptation to perceived forces that are mediated by N-cadherin and matrix adhesions. Intriguingly, myocytes conform to a physiological phenotype when they are cultured on gels mimicking myocardial tissue elasticity. Engineering cardiac myocytes using standardized micropatterned geometries as a means of controlling boundary conditions was used to map the distribution of mechnosensory proteins associated with the N-cadherin complex, demonstrating that α-catenin is a key adaptor protein.
Relating the results of in vitro studies in which cells are cultured on inert non-biocompatible synthetic materials to the function of cells within biologically relevant gels of equivalent stiffness in vivo is not obvious. Hyaluronan, an ECM glycosaminoglycan component widely expressed during cardiac development and disease, was used to engineer a physiologically relevant biosynthetic gel system displaying linear mechanical properties. Remarkably, myocytes cultured on a stiffness far below that of the normal cardiac tissue exhibited a developmental hypertrophic response with well assembled sarcomeric architecture. Ordinarily, at this elastic modulus myocytes atrophy and lose their normally appearing phenotype. Importantly, it was uncovered that the hyaluronan receptors (CD44 and RHAMM) are able to 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 and is reported here for the first time. The results from this study provide a mechanistic explanation for the involvement of hyaluronan in cardiac hypertrophy associated with development, physiologic adaptation and disease.
In conclusion, the results from this Thesis can 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.
Biosketch:
Directions:
The Bossone Research Enterprise Center is located at the corner of 32nd and Market Streets.
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