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Role of microglia-derived factors in glial scar formation and axonal regeneration failure after spinal cord injury

Principal Investigator:
  • Steve Lacroix, Université Laval
  • Barbara Turnbull Foundation for Spinal Cord Research

Project Overview

The role of microglia in spinal cord injury (SCI) has remained obscure for decades. Microglia, the resident immune cells of the brain and spinal cord, were historically perceived as harmful to neurons and their supporting cells (collectively termed as glial cells) in the context of injuryHowever, the possibility remains that microglia may have been confused in previous research with macrophages that infiltrate the site of SCI from the bloodstream and adopt many of the same markers and behaviors. A recent study of ours published in Nature Communications (2019) has shed some light on this important issueshowing that these two cell populations play different roles in SCI. Our work highlighted the importance of microglia in the development of scar tissue around the site of injury, allowing for the containment of inflammation spread to neighboring healthy cells, which would result in bystander tissue damageThe critical time window for the establishment of this beneficial role of microglia was evident during the first week post-SCI. To summarize our previous work, microglia were found to act as an interface between astroglia on the healthy tissue side and fibroblasts on the injury side that will later form the astrocytic and fibrotic scars, respectivelyImportantly, the beneficial effect of microglia was preceded by their activation, accumulation and proliferation around the site of injury, where they secreted growth factors such as insulin-like growth factor-1 (IGF1) and transforming growth factor beta 1 (TGF-ß1)This led to the following HYPOTHESIS: IGF-1 and TGF-ß1, alone or in combination with other microglia-derived molecules, regulate the proliferation of astrocytes and fibroblasts and promote both astrocytic and fibrotic scar formation, thus preventing a wave of secondary degeneration affecting neurons and myelin-forming cells (termed oligodendrocytes) located close to the traumaSupporting this hypothesiswe showed that eliminating microglia resulted in greater tissue damage and impairment in locomotor function. We will therefore investigate how IGF-1 and TGF-ß1 derived from activated microglia mediate scar formation in the injured spinal cord and how this will overall impact secondary degeneration and axonal regeneration responses.