To scar or not to scar : origin and function of fibrotic tissue in the central nervous system

After injury, the adult mammalian central nervous system lacks long-distance axon regeneration, and insufficient repair results in the formation of a multicellular and compartmentalized scar. A great body of work has been dedicated to the study of the glial component of the scar, while the fibrotic lesion core has received less attention. This thesis aims to deepen our knowledge on the cellular origin and function of fibrotic scar tissue following central nervous system injury and disease. In Paper I we revealed that a subset of perivascular cells lining the vasculature, termed type A pericytes, is the major source of stromal fibroblasts that constitute the extracellular matrixrich fibrotic component of the central nervous system scar following spinal cord injury in the mouse. Maximal genetic inhibition of proliferation by type A pericytes largely abolished fibrotic scar tissue generation and resulted in unsealed lesions and impaired wound healing, highlighting the importance of pericyte-derived scarring in regaining tissue integrity and wound closure. On the other hand, moderate inhibition of type A pericyte proliferation preserved wound closure and resulted in attenuated fibrotic scar tissue generation. This represented an attractive scenario to investigate the role of pericyte-derived scarring in axonal regeneration and functional recovery after spinal cord injury. In Paper II we demonstrated that attenuation of pericyte-derived scarring is accompanied by decreased fibrosis, extracellular matrix deposition, astrogliosis and inflammation, and promoted regeneration of raphespinal and corticospinal tract axons caudal to the lesion. Corticospinal tract axons found below the injury site established functional synapses with local spinal neurons. Recovery of sensorimotor function was improved in animals with reduced pericyte-derived scarring. These results established pericyte-derived scarring as a therapeutic target to improve recovery following central nervous system injury. In Paper III we asked whether generation of periycte-derived scar tissue is preserved across diverse central nervous system lesions. In addition to traumatic spinal cord injury, we found that type A pericyte progeny detached from the vascular wall and generated fibrotic scar tissue, or contributed to tumor stroma, after traumatic brain injury, inflammatory demyelinating disease and in a glioblastoma tumor model, respectively. Following cerebral ischemic stroke, type A pericytes increased