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

Fibrotic scar formation caused by stromal cells is often associated with chronic, non-healing pathology impeding repair of the central nervous system (CNS). Perivascular fibroblasts (PVFs) in the perivascular space are activated, express and deposit excess collagen I (Col I), and form a fibrotic scar following CNS disease. Here we show that blood-derived fibrinogen deposition in the perivascular space following photothrombosis, a mouse model for ischemic stroke, initially induces PVF activation. Pharmacological fibrinogen depletion reduces PVF activation and migration away from blood vessels to build up the fibrotic scar. Fibrinogen-induced beta1 integrin signaling in PVF regulates Col I expression. Single-cell RNA sequencing and genetic approches revealed a contribution of fibrinogen-induced myeloid cells to PVF activation. Fibrinogen depletion abrogates PVF-astrocyte signaling and lesion border formation, promoting neuronal survival and plasticity. We propose that fibrinogen is a critical trigger for fibrotic scar formation, inhibiting neuronal regeneration after stroke.