Citation

The central nervous system does not undergo significant amounts of regeneration following injury. Despite this, cellular repair processes occur that help to limit the spread of injuries, maintain tissue integrity, and in some cases regenerate lost cells. Here I introduce central nervous system fibroblasts as regulators of regenerative processes in the central nervous system, and present aging and exercise as factors regulating fibroblasts and the lesioned environment. Fibroblasts are connective tissue cells that are found throughout the body. Under pathological conditions they contribute to tissue scarification by secreting excessive amounts of extracellular matrix that impairs regeneration. Fibroblasts in the central nervous system are normally found at the border regions in the meninges, perivascular space, and choroid plexus. In the injured central nervous system fibroblasts are elevated in the parenchyma and impair regenerative processes like axon regeneration. In this thesis I characterized the elevation of fibroblasts in the toxin induced lysolecithin model of central nervous system injury. One primary observation was the association of fibroblasts with microglia/macrophage responses, as well as the ability of macrophages to promote fibroblast migration in vitro. Central nervous system fibroblasts spatially obscured newly myelinating oligodendrocytes in lysolecithin lesions and inhibited the differentiation of oligodendrocyte progenitor cells in vitro. I explored the impact of age on the fibroblast response to lysolecithin injury. I found that age affected the proportion of the lysolecithin lesion occupied by fibroblasts, attenuated the immune response, and ablated the chemoattractant capacity of macrophages in vitro. Lastly, I described the changes that occur in the proteome of naïve and lysolecithin lesioned spinal cords and serum from exercising and sedentary mice. I also examined the effects of exercise on the young and middle-aged fibroblast response. I found that acute voluntary access to a running wheel resulted in significant protein changes related to metabolism, oxidative stress, and synaptic transmission. However, voluntary wheel running did not result in any changes to the fibroblast response in lysolecithin lesions in young and middle-aged mice. This thesis highlights the role of fibroblasts in central nervous system injuries, details the potential causes and outcomes of their elevation in the parenchyma, and also highlights the implications of aging and exercise for the fibroblast response and broader lysolecithin lesion environment.