Date on Master's Thesis/Doctoral Dissertation

5-2025

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Degree Program

Physiology and Biophysics, PhD

Committee Chair

Hill, Bradford

Committee Member

Jones, Steven

Committee Member

Metz, Cynthia

Committee Member

LeBlanc, Amanda

Committee Member

Maldonado, Claudio

Committee Member

Brainard, Robert

Author's Keywords

cardiovascular disease; fibroblasts; inflammation; cardiac remodeling

Abstract

Immediately following myocardial injury, a robust reparative response is orchestrated through intercellular communication. While various cell populations play critical roles in this process, cardiac fibroblasts have long been recognized as essential mediators of collagen synthesis and scar maturation; however, recent investigations have uncovered significant heterogeneity within the cardiac fibroblast population, revealing distinct subpopulations with roles that extend beyond their traditional functions. Notably, after tissue injury, fibroblasts exposed to damage signals can transition to an inflammatory phenotype, utilizing paracrine and autocrine signaling to coordinate immune cell recruitment and activation. Yet, the mechanisms underlying inflammatory cardiac fibroblast differentiation and their influence on cardiac remodeling after injury remains poorly understood. Among the pathways that could propagate inflammatory signaling, TGF-β activated kinase 1 (TAK1) appears to be a conspicuous candidate with the capacity to coordinate downstream mediators involved in inflammatory responses. In this dissertation, we tested the central hypothesis that TAK1 signaling drives inflammatory cardiac fibroblast differentiation to regulate the inflammatory response following cardiac injury. Because little is known about how cardiac fibroblasts respond to inflammatory ligands, we first examined the signaling pathways activated and the functional changes induced by ligand-receptor interactions. Chapter II delves into these findings in detail, examining the extent to which these responses are regulated by TAK1 activity. Our findings demonstrate that exposure to pro-inflammatory ligands, such as IL-1β, activates inflammatory and stress signaling pathways, leading to distinct changes in gene expression profiles. Notably, these changes were abrogated with TAK1 knockdown. Functional analyses revealed that IL-1β treatment enhanced cellular energetics, increased chemokine translation and secretion, and reduced extracellular levels of pro-resolving lipid mediators. Interestingly, TAK1 knockdown had opposing effects on chemokine and lipid mediator secretion, promoting a pro-resolving, anti-inflammatory secretome profile. To better describe the role of the inflammatory cardiac fibroblasts in an in vivo system, we investigated the effects of disrupted fibroblast-specific TAK1 activity in the context of myocardial infarction (MI) (Chapter III). In male mice, impaired TAK1 signaling in fibroblasts resulted in improved functional outcomes and reduced fibrotic burden. The speculation that altered TAK1 signaling in fibroblasts led to attenuated inflammation during the acute repair phase is supported by data showing reduced immune cell populations at 3-days post-MI. In contrast, while no significant functional (e.g., ejection fraction, cardiac output) or structural changes (e.g., scar mass, wall thickness) were observed in the female cohort, fibroblast-specific TAK1 suppression was associated with increased mortality rates, highlighting potential sex-specific differences in the role of TAK1 signaling in response to MI. We next assessed whether the beneficial effects of suppressed fibroblast-TAK1 activation observed during post-MI repair extend to models of chronic cardiac stress, such as pressure overload. In Chapter IV, we show that reduced fibroblast-TAK1 activation does not significantly influence chronic pathological remodeling, as no changes in cardiac function or fibrotic progression were observed in either male or female mice. Collectively, the findings of this work offer novel insights into TAK1 as a key regulator in the acquisition of the inflammatory cardiac fibroblast phenotype. Our data highlights the critical role of these cells in post-MI repair, where their contributions to acute inflammation significantly influences long-term cardiac remodeling and recovery.

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