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

TL;DR

This study shows that fibrinogen, a blood protein, triggers scar formation after stroke by activating fibroblasts, which hinders brain repair.

Contribution

The paper identifies fibrinogen as a key driver of fibroblast activation and scar formation in ischemic stroke.

Findings

Fibrinogen deposits in the perivascular space after stroke and activates fibroblasts.

Fibrinogen-induced myeloid cells contribute to fibroblast activation via β1 integrin signaling.

Fibrinogen depletion reduces fibrotic scarring and promotes neuronal survival and plasticity.

Abstract

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.

•Cortical injury leads to immediate fibrinogen deposition in the perivascular space•Fibrinogen induces PVF activation and Col I expression via β1 integrin signaling•Fibrinogen-induced myeloid cell activation contributes to PVF activation•Fibrinogen orchestrates lesion border formation, hindering neuronal regeneration

Cortical injury leads to immediate fibrinogen deposition in the perivascular space

Fibrinogen induces PVF activation and Col I expression via β1 integrin signaling

Fibrinogen-induced myeloid cell activation contributes to PVF activation

Fibrinogen orchestrates lesion border formation, hindering neuronal regeneration

Physiology; Neuroscience; Cell biology

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