Prior to clinical evidence of fibrosis, microvascular injury occurs, presenting as an altered functional state of the endothelium, increased permeability, enhanced vasoreactivity, increased expression of adhesion molecules, excessive inflammation, and altered vascular wall growth. Microvascular rarefaction, or capillary dropout, is coincident with chronic fibrosis, and considered an accelerator of the disease. However little is known about the microvascular contribution to fibrotic diseases in which microvasculature are key to tissue health and homeostasis. Given the central role of the vasculature in barrier function, inflammatory regulation and interstitial tissue necrosis, it is likely that the microvasculature, specifically, mural perivascular cells (pericytes), are key contributors to fibrotic development and progression. Recent evidence suggests that microvascular dysfunction may be more directly influential to tissue remodeling than epithelial cells. Limited availability of human pericytes from a readily available human source has led to an incomplete understanding of the mechanisms underlying pericyte to myofibroblast transition that facilitate both microvascular and interstitial matrix remodeling. Our work, supported by that of others in this area, has led us to the hypothesis that pericytes cease homeostatic maintenance of the microvasculature by transition into a myofibroblast through the process of dedifferentiation and re-differentiation known as cellular reprogramming. As myofibroblasts, cells of pericyte lineage contribute to interstitial tissue fibrosis. Through three distinct aims we will show that, in response to growth factor, pericytes deposit extracellular matrix proteins to alternatively support vascular stability and fibrosis as they undergo phenotypic transition from microvascular pericytes to interstitial myofibroblasts. We also determine points in pericyte transition that may be key for therapeutic intervention. We utilize traditional molecular biology methods and biomaterials technology to determine the profibrotic mediators promote functional and phenotypic shifts in pericytes. Using 2- and 3-D bioengineered mechanically and biochemically tunable polymer based extracellular matrices, we decouple the role of biochemical and mechanical signals in regulation of PC to myofibroblast transition through the process of reprogramming. Results acquired through use of human cells in bioengineered structures will be validated with animal models of pulmonary fibrosis.

Project Narrative: The lack of knowledge surrounding the role of human pericytes in microvascular homeostasis and fibrosis have prevented us from developing appropriate therapeutic strategies that will prevent the genesis, progression and dysfunction of tissues that are affected by fibrosis. Therefore, this proposal describes the investigation of mechanisms that facilitate pericyte remodeling of the vascular wall and interstitial tissue in support of tissue health and dysregulation. This work will translate basic understanding of pericyte biology to therapeutic intervention for fibrotic disorders of pericyte abundant tissue, including the lung, skin, heart, kidney and liver.