Date on Master's Thesis/Doctoral Dissertation
8-2024
Document Type
Doctoral Dissertation
Degree Name
Ph. D.
Department
Biochemistry and Molecular Biology
Degree Program
Biochemistry and Molecular Biology, PhD
Committee Chair
Moore IV, Joseph
Committee Member
Jones, Steven
Committee Member
Gregg, Ronald
Committee Member
Samuelson, David
Committee Member
Smith, Melissa
Author's Keywords
Fibrosis; myocardial infarction; extracellular matrix; heart failure; matricellular proteins; fibroblast
Abstract
Expansion of the extracellular matrix (ECM), known as fibrosis, accompanies nearly all forms of cardiac disease; however, its most significant and complex manifestations arise following a myocardial infarction (MI). This process, principally led by fibroblasts, constitutes a necessary and adaptive response acutely to fill the void from cardiomyocyte necrosis following ischemic injury due to the heart’s lack of regenerative capacity. This acute response never fully resolves and contributes to ongoing collagen accumulation in non-infarcted regions, leading to diminished ventricular compliance, ongoing myocyte loss, and attrition in function—culminating in heart failure. Further, recent research demonstrates that concomitant with progressive increases in collagen accumulation, there are also increments in collagen alignment in the failing heart; however, the implications of this structural reorganization are understudied and not known. Despite years of studies dedicated to understanding the process of fibrosis, there are no therapies to prevent its progression; however, cardiac cell therapy, while originally introduced with the promise of promoting regeneration, has been shown to restrict the fibrotic response in MI. The molecular underpinnings and features that contribute to enhanced anti-fibrogenic signaling potency in cells used for cell therapy is not understood. We identified a family of matricellular proteins, cellular communication network factors (CCNs), secreted by these cells as potential factors responsible for heightened anti-fibrogenic capacity of donor cells. CCNs are heavily implicated in the modulation of the fibrotic response across multiple pathologies, which fueled investigations into how CCNs regulate endogenous fibroblast-led extracellular matrix remodeling in the failing heart. This research delves into the intricate interplay among fibrosis, cardiac cell therapy, and the matricellular protein, cellular communication network factor 1 (CCN1). This work aimed to elucidate two objectives: 1) assess to what extent donor cell cardiomyogenic lineage-commitment underlie the therapeutic efficacy of cardiac cell therapy in improving chronic ischemic heart failure, and 2) investigate the involvement of CCN1 in facilitating fibroblast-mediated structural remodeling of the collagenous scar post-MI. We identified CCN1 as a pivotal arbiter of scar collagen architecture, fortifying its integrity by orchestrating interactions between the fibroblasts and the matrix. This research explores the underappreciated domain of fibroblast-driven structural remodeling post-MI, with implications for targeted therapeutic interventions aimed at fortifying scar resilience and integrity. By unraveling the intricate dynamics of cardiac fibrosis and its modulation through cell therapy and CCN1, this work opens the possibilities for innovative strategies in managing cardiac ailments and advancing patient outcomes.
Recommended Citation
Fischer, Annalara Garland, "Unraveling the complex dynamics of cardiac fibrosis: CCN1 as a novel regulator of scar collagen architecture and structural integrity in myocardial infarction." (2024). Electronic Theses and Dissertations. Paper 4420.
Retrieved from https://ir.library.louisville.edu/etd/4420
