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.

Astrocytes in human central nervous system diseases: a frontier for new therapies

“…19,65 Although most border-forming reactive astrocytes in narrow zones immediately abutting tissue lesions are newly proliferated, proliferation drops off rapidly with increased distance from lesions, which are surrounded by large areas of intermingled proliferative and non-proliferative reactive astrocytes as well. 67,75 Most border forming astrocytes derive from local astrocytes, 67 with a small contribution from proliferation of adult OPC. 76,77 Proliferation of astrocytes is an indispensable part of reactive astrogliosis, and suppression of proliferation exacerbates damage and delays wound closure.…”

“…6 reactive cells (border-forming astrocytes and amoeboid microglia) concentrating at the lesion perimeter, or even entering (reactive microglia) the lesion core. 75,169,170 Reactive microglia first position themselves between the infiltrating lymphocytes and newly proliferating reactive astrocytes that will form the perilesional border of astrocytes. [171][172][173] Less prominent reactive morphotypes represented by polarised cells, which extend their processes toward the lesion area, are positioned more distantly, whereas healthy looking neuroglia demarcate the undamaged tissue.…”

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].…”