Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system in which the body?s immune system attacks the myelin sheath that surrounds and insulates the axons of neurons. In many cases this myelin is not repaired by oligodendrocyte lineage cells leading to long term disability. One hypothesis as to why myelin is not repaired is that there is a physical barrier preventing oligodendrocyte lineage cells from interacting with axons and repairing the damaged myelin. Following spinal cord injury, a scar forms around the site of trauma and seals off the injured and inflamed tissue. The scar consists of an outer glial scar made up of reactive astrocytes and an inner fibrotic scar made of extracellular matrix proteins. The glial scar has been studied extensively as a potential therapeutic target for CNS trauma, but much less is known about the origins and role of the fibrotic scar. In MS, the glial scar has also been characterized, and fibrosis in human tissue reported, but the role of a fibrotic scar has not been investigated. To test for the presence of a fibrotic scar in neuroinflammatory lesions, mice were induced with experimental autoimmune encephalomyelitis (EAE), which leads to the formation of neuroinflammatory demyelinated lesions and is used as a mouse model of MS. An extensive fibrotic scar was present in the lesioned tissue that remained for months following symptom onset and arose from the proliferation of collagen-expressing fibroblasts. Nothing is known about the role this fibrotic scar plays in repair following neuroinflammatory lesion formation and the signals that activate scar formation. The goal of this project is to define the role of the fibrotic scar in repair following neuroinflammatory lesion formation and the molecular mechanisms that cue its formation, with the hopes of identifying potential therapeutics to manipulate the scar in vivo. The hypothesis to be tested is that the fibrotic scar that forms following EAE induction prevents repair and forms through TGF? pathway activation in fibrotic cells. First, the role of the scar in EAE repair in vivo will be determined by preventing the fibrotic scar from forming through the ablation of dividing fibrotic cells following EAE induction. To determine if TGF? pathway activation is necessary for scar formation, a fibroblast- specific Cre mouse line will be used to conditionally knockout key signaling TGF? pathway genes prior to scar formation. Additionally, to study how TGF? signaling regulates the proliferation, collagen production and migration of CNS fibroblasts, recombinant TGF? and pathway inhibitors will be added to a primary, in vitro cell model.
This project aims to determine the role of the fibrotic scar in tissue repair following neuroinflammatory conditions such as multiple sclerosis (MS). This scar can be found surrounding blood vessels in human MS tissue and throughout demyelinating lesions in mice induced with EAE, a MS mouse model, and may physically block tissue repair and regeneration. The outcomes of this project have the potential to lead to new therapeutics that could aid in repair in neuroinflammatory diseases such as MS.
