The Role of the Fibrotic Scar in Repair Following Neuroinflammation Cayce Dorrier1, Ezekiel Haenelt1, Richard Daneman1 1UCSD Departments of Pharmacology and Neurosciences
Multiple sclerosis (MS) is a neuroinflammatory disease of the central nervous system (CNS) 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 myelinating oligodendrocytes, which decreases the efficiency of action potential conduction and leads to neural dysfunction. We hypothesized that a barrier preventing oligodendrocyte lineage cells from interacting with and repairing the damaged myelin is a fibrotic scar. Following CNS injury, a scar consisting of an outer glial scar made up of reactive astrocytes and an inner fibrotic scar made of fibrotic proteins such as collagen I forms around the site of trauma. While these scars prevent toxins and immune cells from exiting areas of blood-brain barrier breakdown, they remain a barrier for axonal regeneration. In MS the glial scar has also been characterized, but the presence and role of a fibrotic scar have not been investigated. I have shown that following induction of experimental autoimmune encephalomyelitis (EAE) in mice, which leads to the formation of neuroinflammatory lesions experiencing demyelination and is used as a mouse model of MS, an extensive fibrotic scar forms in the lesioned tissue. Scar-forming cells were visualized in this lesioned tissue using a Col1a1GFP mouse model. The number of these cells increased in the lesion site following symptom onset and peaked shortly after the peak of motor disability. The objective of this project is to define the molecular mechanisms that cue fibrotic scar formation, with the hopes of identifying potential therapeutics to manipulate the scar in vivo. To understand the signaling pathways that play a role in scar formation, I analyzed the transcriptional profile of CNS fibroblasts from healthy mice and mice with EAE. Specifically, I used fluorescence activated cell sorting to purify these cells from the spinal cords of Col1a1GFP control mice and mice with EAE at the onset of scar formation and during chronic scarring and analyzed their transcriptome by RNA sequencing. I found that these cells are significantly enriched in the expression of pathways including focal adhesion and extracellular matrix-receptor interactions in comparison to whole spinal cord tissue. Many of these enriched, matrix-related genes increased in expression throughout the time course of disease while a subset of signaling components peaked in expression at the onset of scar formation. I am currently using this data to identify potential targets for therapeutics aimed at manipulating scar formation in a primary, in vitro CNS fibroblast model that I have developed and optimized.
This work is funded by the NIH T32 Pharmacological Sciences Training Grant
Credits: None available.
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