Fibroblasts are an interstitial mesenchymal cell population required for maintenance, remodeling, and repair of the extracellular matrix. Upon tissue injury or insult, fibroblasts transiently activate to repair damaged tissue. Following injury resolution, these cells either inactivate or go through apoptosis. However, if their activation is left sustained, these cells can lead to fibro-contractile pathologies such as idiopathic pulmonary fibrosis (IPF). IPF is characterized by distal scarring of the lung distorting healthy alveolar architecture and replacing it with dense extracellular matrix (ECM) severely disrupting gas-exchange function. Current therapies for IPF are noncurative and only slow the rate of decline of IPF patients. Thus, there is a critical need to further understand the molecular mechanisms driving fibroblast activation to potentially therapeutically intervene and improve patient outcomes.

Fibroblast in vivo are subjected to biochemical stimuli, such as TGF-β or PDGF, and biomechanical stimuli, such as matrix stiffness, both of which potently mediate activation of fibroblasts in culture. These signals ultimately integrate into a transcriptional response which drives fibroblast activation. Understanding the pathological epigenetic mechanisms facilitating this transcriptional response could lead to therapies to reverse tissue-fibrosis. The work within this thesis investigates epigenetic mechanisms facilitating fibroblast activation in vitro and in vivo.

Specifically, this thesis is focused on three aims:​ (i) understanding mechanistically how TGF-β signaling utilizes HDAC function to drive activation, (ii) investigating how matrix stiffness epigenetically alters freshly-isolated lung fibroblasts and identifying the transcriptional regulators involved in this process, and (iii) using a transgenic lineage-labeling approach, evaluating how bleomycin-induced mouse lung fibrosis epigenetically activates fibroblasts in vivo. These three aims address key gaps in the literature in understanding mechanisms facilitating persistent activation of fibroblasts driving tissue-fibrosis and lay the conceptual framework with which future studies can be built on to bring these discoveries closer to clinical translation.