Fibrinogen induces neural stem cell differentiation into astrocytes in the subventricular zone via BMP signaling

Lauriane Pous,Dietmar Pfeifer,Sachin S Deshpande,Katerina Akassoglou,Könül Topp,Soroush Doostkam,Christian Bohrer,Subash C Malik,Francisco Fernández-Klett,Dennis K Galanakis,Verdon Taylor,Sebastian Schildge,Christian Schachtrup,Szilvia Mezey,Suvra Nath

doi:10.1038/s41467-020-14466-y

Abstract

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.

Highlights

Neural stem/progenitor cells (NSPCs) originating from the subventricular zone (SVZ) contribute to brain repair during central nervous system (CNS) disease
Since the SVZ vascular system is already permeable for circulating small molecules under homeostatic conditions[7], we examined whether blood components enter the SVZ stem cell niche environment and alter NSPC differentiation in vivo using different mouse models of CNS injury
Fibrinogen deposition was significantly evident in the SVZ stem cell niche after middle cerebral artery occlusion, the mouse model for stroke as well as in the SVZ of human brain sections after stroke (Fig. 1c, d, Supplementary Fig. 1e), suggesting that fibrinogen deposition in the SVZ stem cell niche environment is a general feature in stroke

Summary

Introduction

Neural stem/progenitor cells (NSPCs) originating from the subventricular zone (SVZ) contribute to brain repair during CNS disease. Fibrinogen inhibited neuronal differentiation in SVZ and hippocampal NSPCs while promoting astrogenesis via activation of the BMP receptor signaling pathway. We propose that fibrinogen is a regulator of NSPC-derived astrogenesis from the SVZ niche via BMP receptor signaling pathway following injury. Understanding how central nervous system (CNS) disease alters the SVZ stem cell niche environment and the release of blood-derived factors and how these factors regulate NSPC cell fate is instrumental for harnessing these cells for brain repair. Our results demonstrate that the circulating blood-derived factor fibrinogen induces an astrogenic milieu in brain stem cell niches that may determine the contribution of NSPCs in repair mechanisms in CNS disease

Methods

Results

Conclusion