Fibrosis, defined by the deposition of collagen I, is a devastating pathological event that occurs in many organs including the heart, kidney, liver and lung in response to injury and inflammation. This fibrotic response inhibits recovery inflammation and can even lead to organ failure. Despite the potential importance, very little is known about whether there is a fibrotic response in the central nervous system (CNS) following neuroinflammation that occurs in diseases such as multiple sclerosis, neuromyelitis optica, stroke and CNS infections, and how this response affects repair and recovery. Using experimental autoimmune encephalomyelitis (EAE), a mouse model of neuroinflammation, we have identified that a robust collagen I- based fibrotic scar forms covering the neuroinflammatory lesion and we hypothesize that this fibrotic scar inhibits the ability of reparative cells to enter the lesion. In preliminary studies using lineage tracing and single cell sequencing, we have identified that this fibrotic scar is formed by the activation and proliferation of fibroblasts. We have further generated methods to isolate and culture CNS fibroblasts providing an in vitro model to study the proliferation, migration and collagen 1 production from these cells. In this proposal we aim to determine whether the fibrotic scar is helpful or harmful for recovery following neuroinflammation and to further study the mechanisms that regulate fibrotic scar formation. We will first determine whether inhibition of fibrotic scar formation can lead to an increased recovery from EAE. We will then examine whether TGF? and PDGFR signaling pathways regulate fibrotic scar formation. We hypothesize that TGF? signaling drives the proliferation and collagen I production by the fibroblasts and that PDGFR signaling regulates the migration of the fibroblasts to the lesion. Our goal is to determine whether modulating the fibrotic scar is a potential therapeutic target to aid in recovery for patients with neuroinflammatory diseases.
Fibrosis is a common and debilitating physiological response to injury and inflammation in many tissues and organs, however very little is known about whether there is a fibrotic response to inflammatory diseases of the central nervous system (CNS) including multiple sclerosis, neuromyelitis optica, stroke, and CNS infections. We have identified that a robust fibrotic scar forms in response to CNS neuroinflammatory lesion formation and we will test the hypothesis that a fibrotic scar limits repair following neuroinflammatory disease. We will further examine the molecular mechanisms that lead to fibrotic scar formation, with the goal of identifying potential therapeutics to aid in repair following neuroinflammatory disease.
