Fibrinogen triggers intial perivascular fibroblast activation in a mouse model of cortical ischemic stroke

Perivacular fibroblasts (PVFs) in the perivascular space delaminate from blood vessels, expand, express and deposit an excess of collagen I (Col I) and become an integral component of the fibrotic scar after central nervous system (CNS) disease. Here, we show that blood-derived fibrinogen deposition in the perivascular space initially induces PVF activation after photothrombosis, a mouse model of ischemic stroke. Pharmacological fibrinogen depletion reduces PVF activation and their delamination from blood vessels to build up the fibrotic scar. Fibrinogen induces beta1 integrin signaling in PVF to induce Col I expression and secretion. Single-cell RNA sequencing (scRNA-Seq) and genetic approches revealed a contribution of fibrinogen-induced perivascular macrophages to PVF activation. Finally, fibrinogen depletion abrogates PVF-astrocyte signaling and astrocyte lesion border formation, promoting neuronal survival and plasticity. Therefore, we propose that fibrinogen is a critical trigger for PVF activation and fibrotic scar formation, inhibiting neuronal regeneration after stroke.