Cellular mechanisms of perivascular fibroblast development and dependence on PDGF signaling

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PROJECT SUMMARY Perivascular spaces (PVSs) are fluid-filled spaces surrounding vessels of the central nervous system, are thought to have important roles in maintenance of brain health, and are a unique niche for a variety of perivascular cell types. A cell type of particular interest is perivascular fibroblasts (PVFs) which are poorly characterized, and their functions are largely unknown. PVFs are known to reside on the outside the vascular smooth muscle layer of medium-to large-diameter vessels in the adult mouse central nervous system, and are primarily identified by expression of Collagen-1 and Platelet-derived growth factor receptor (PDGFR)a and PDGFRb. However, nearly nothing is known about the developmental origins, or the cellular and molecular mechanisms important for PVF development. Preliminary data suggests PVFs emerge from a population of cells in the meninges and gradually populate brain PVSs during postnatal development, but this has not yet been investigated further. These gap in knowledge is a major barrier to developing novel tools to investigate the role of PVFs in brain homeostasis and disease. The objective of this proposal is to investigate the developmental origins, cellular dynamics, and molecular signaling mechanisms involved in PVF development. In Aim 1, I will use a combination of transgenic mouse lines that label PVFs, optical tissue clearing, ex vivo imaging, and a multi-color lineage tracing reporter to investigate the cellular origins and dynamics of developing PVFs. In Aim 2, I will use intracisternal cerebrospinal fluid tracer assays to determine the relationship between the timing of PVF development and PVS function. Finally, in Aim 3 I will investigate PDGF signaling as a potential mechanism controlling PVF development. Together, this project will be the first to fully characterize how PVF development occurs and whether or not PDGF signaling is involved.