Fibrinogen regulates lesion border‐forming reactive astrocyte properties after vascular damage

Abstract

Reactive astrocytes at the border of damaged neuronal tissue organize into a barrier surrounding the fibrotic lesion core, separating this central region of inflammation and fibrosis from healthy tissue. Astrocytes are essential to form the border and for wound repair but interfere with neuronal regeneration. However, the mechanisms driving these astrocytes during central nervous system (CNS) disease are unknown. Here we show that blood‐derived fibrinogen is enriched at the interface of lesion border‐forming elongated astrocytes after cortical brain injury. Anticoagulant treatment depleting fibrinogen reduces astrocyte reactivity, extracellular matrix deposition and inflammation with no change in the spread of inflammation, whereas inhibiting fibrinogen conversion into fibrin did not significantly alter astrocyte reactivity, but changed the deposition of astrocyte extracellular matrix. RNA sequencing of fluorescence‐activated cell sorting‐isolated astrocytes of fibrinogen‐depleted mice after cortical injury revealed repressed gene expression signatures associated with astrocyte reactivity, extracellular matrix deposition and immune‐response regulation, as well as increased gene expression signatures associated with astrocyte metabolism and astrocyte‐neuron communication. Systemic pharmacologic depletion of fibrinogen resulted in the absence of elongated, border‐forming astrocytes and increased the survival of neurons in the lesion core after cortical injury. These results identify fibrinogen as a critical trigger for lesion border‐forming astrocyte properties in CNS disease.

Heterogeneity of brain extracellular matrix and astrocyte activation

“…First observed over 100 years ago (Sofroniew, 2015), and originally termed “glial scar”, and approximated by the A2 phenotype, the mechanisms required to induce BFRA are only beginning to emerge. Recent evidence suggests fibrinogen is a necessary inducer (Conforti et al., 2022) but the authors noted that replacing fibrinogen with fibrin did not change the level of astrocyte activation but did alter the profile of astrocytic ECM proteins. BFRA are newly proliferated astrocytes expressing GFAP and vimentin (Sofroniew, 2020), have dense populations of focal adhesions, and are therefore highly sensitive to their substrate stiffness and are associated with a myofibroblastic phenotype (Vedrenne et al., 2017).…”

Astroglial Cells: Emerging Therapeutic Targets in the Management of Traumatic Brain Injury

“…The structure of glial scar tissue consists of a lesion core and the penumbra, otherwise known as the cortical peri-infarct area [24]. Reactive astrocytes form scar tissue in the penumbra region [136,137]. Within the days following injury, the amount of reactive astrocytes increases around the site of the lesion [138].…”

Dissecting glial scar formation by spatial point pattern and topological data analysis

“…The scar is primarily composed of reactive astrocytes, activated microglia, and polydendrocytes/NG2 + cells, which rearrange spatially to establish a demarcated, yet dynamic, barrier around the lesioned tissue (Wanner et al 2013; Hackett and Lee 2016; Bellver-Landete et al 2019; Zhang et al 2022). This enables compartmentalization of the injured tissue (Conforti et al 2022) to limit the spread of toxic and inflammatory mediators towards healthy regions (Voskuhl et al 2009; Yoshizaki et al 2021). The organization of reactive glia affects the structural and functional integrity of the lesioned tissue, making processes such as axonal sprouting and neurovascular repair a vital target for therapeutic interventions (Anderson et al 2016; Fu et al 2020).…”