Cellular Behaviors of Perivascular Fibroblasts in Cerebral Ischemia

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Regaining brain function is crucial to improve patient recovery following stroke. An ischemic event in the brain limits oxygen and nutrient supply resulting in neuronal cell death and a robust inflammatory response. Following clearance of the necrotic tissue the lesion undergoes a wound healing processes ultimately resulting in the formation of a fibrotic scar. The fibrotic scar impedes neuronal regeneration thus impacting recovery and function of the damaged tissue. The contributing cell types that promote fibrotic scar formation following stroke are poorly understood. Addressing these gaps in knowledge will allow us to identify the pro-fibrotic cell types and better poise us for testing mechanisms that contribute to fibrosis following CNS injury. Understanding these important aspects of stroke could provide a potential for developing therapeutics aimed at limiting scar formation and supporting neuronal regeneration following stroke. Recent studies have identified Pdgfrβ-expressing cells as the potential pro-fibrotic cell type following CNS injury. The identity of the Pdgfrβ-expressing cells, however, is not clear. Strong evidence points to Pdgfrβ- expressing perivascular fibroblasts (PVFs) as major contributors to the fibrotic scar. On the other hand, Pdgfrβ+ pericytes are also suggested to promote fibrotic scar formation. However, pericytes are generally sensitive to hypoxia and inflammation and likely undergo apoptosis following CNS injury. Based on this, I hypothesize that perivascular fibroblasts are a unique population of perivascular cells in the brain and significantly contribute to the fibrotic scar following cerebral ischemia. Using in vivo two-photon microscopy to simultaneously visualize pericytes and PVFs I will test this hypothesis in two distinct aims. In Aim 1, I will study the topological relation of PVFs to pericytes along the cerebrovascular network, define their morphological characteristics, and test the role of PVFs in vascular stability in the healthy brain. In Aim 2, I will characterize the cellular behaviors of PVFs and pericytes following cerebral ischemia to determine which cell type substantially contributes to the fibrotic scar. I will also pharmacologically inhibit PDGF signaling to determine if this pathway plays a significant role in the activation of PVFs during cerebral ischemia. Together these studies will help to elucidate the pro-fibrotic cell type following stroke in animals and determine if PVFs are important for vascular stability in the healthy brain.