Dynamic fibroblast-immune interactions shape wound healing after brain injury

Fibroblasts coordinate the response to tissue injury, directing organ regeneration versus scarring. In the central nervous system (CNS), fibroblasts are uncommon cells enriched at tissue borders, and their molecular, cellular, and functional interactions after brain injury are poorly understood. Here we define the fibroblast response to sterile brain damage across time and space. Early pro-fibrotic myofibroblasts infiltrated CNS lesions and were functionally and spatially organized by fibroblast TGFβ signaling, pro-fibrotic macrophages and microglia, and perilesional brain glia that activated TGFβ via integrin αvβ8. Early myofibroblasts subsequently transitioned into a variety of late states, including meningeal and lymphocyte-interactive fibroblasts that persisted long term. Interruption of this dynamic fibroblast-macrophage-glial coordination impaired brain wound healing and the resolution of neuroinflammation, disrupted generation of late de novo CNS lymphocyte niches, and increased mortality in a stroke model. This work highlights an unexpected role of fibroblasts as coordinate regulators of CNS healing and neuroinflammation after brain injury. ### Competing Interest Statement D.S. and UCSF hold patents on the uses of antibodies that block integrin avb8. D.S. is a founder of Pliant Therapeutics and has received research funding from Abbvie, Pfizer, and Pliant Therapeutics. D.S. serves on the Scientific Review Board for Genentech, and on the Inflammation Scientific Advisory Board for Amgen. The remaining authors declare no competing interests.