Neural stem/progenitor cells (NSPCs) originating from the subventricular zone (SVZ) contribute to brain repair during CNS disease. The microenvironment within the SVZ stem cell niche controls NSPC fate. However, extracellular factors within the niche that trigger astrogliogenesis over neurogenesis during CNS disease are unclear. Here, we show that blood-derived fibrinogen is enriched in the SVZ niche following distant cortical brain injury in mice. Fibrinogen inhibited neuronal differentiation in SVZ and hippocampal NSPCs while promoting astrogenesis via activation of the BMP receptor signaling pathway. Genetic and pharmacologic depletion of fibrinogen reduced astrocyte formation within the SVZ after cortical injury, reducing the contribution of SVZ-derived reactive astrocytes to lesion scar formation. We propose that fibrinogen is a regulator of NSPC-derived astrogenesis from the SVZ niche via BMP receptor signaling pathway following injury.
Stroke is the leading cause of adult disability. Endogenous neural stem/progenitor cells (NSPCs) originating from the subventricular zone (SVZ) contribute to the brain repair process. However, molecular mechanisms underlying CNS disease-induced SVZ NSPC-redirected migration to the lesion area are poorly understood. Here, we show that genetic depletion of the p75 neurotrophin receptor (p75NTR−/−) in mice reduced SVZ NSPC migration towards the lesion area after cortical injury and that p75NTR−/− NSPCs failed to migrate upon BDNF stimulation in vitro. Cortical injury rapidly increased p75NTR abundance in SVZ NSPCs via bone morphogenetic protein (BMP) receptor signaling. SVZ-derived p75NTR−/− NSPCs revealed an altered cytoskeletal network- and small GTPase family-related gene and protein expression. In accordance, BMP-treated non-migrating p75NTR−/− NSPCs revealed an altered morphology and α-tubulin expression compared to BMP-treated migrating wild-type NSPCs. We propose that BMP-induced p75NTR abundance in NSPCs is a regulator of SVZ NSPC migration to the lesion area via regulation of the cytoskeleton following cortical injury.
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.
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