Final Report Summary - FIB (Molecular mechanisms of fibrinogen function regulating NSC differentiation in CNS injury or disease) The vascular system provides brain cells not only with nutrients, but also with non-nutritional signals, such as chemokines, growth factors, and cytokines, that play key roles in the control of the organ growth, morphogenesis and homeostasis. However, circulating blood factors leak into the brain parenchyma in CNS disease and even before any pathological signs of the disease due to blood-brain barrier (BBB) permeability or rupture. Our research interests center on a potential role of the altered vascular system in CNS disease in instructing brain repair.The functions of blood proteins in neuronal repair processes in CNS diseases with vascular rupture are only poorly characterized. My research focuses on the circulating blood protein fibrinogen. The blood protein fibrinogen serves a critical function as the major architectural protein component of blood clots. Fibrinogen mediates diverse biological responses due to a molecular structure that contains binding sites for receptors expressed on cells in the nervous system, and its ability to function as a carrier of growth factors, which makes fibrinogen distinct among other blood proteins. In previous studies my group extended the role of fibrinogen from a coagulation factor to a mediator of blood-brain barrier leakage and neurodegeneration. I was able to show that fibrinogen inhibits neurite outgrowth via β3 integrin-mediated phosphorylation of the EGF receptor and that fibrinogen triggers astrocyte scar formation by regulating active TGF-β bioavailability.A major hurdle for neuronal regeneration is scar formation. Resident astrocytes become hypertrophic and contribute to the inhibitory glial scar segregating damaged and inflamed tissue from adjacent intact tissue and our previous studies identified fibrinogen as a initial inducer of astrocyte activation. In the recent project funded by the European Union, we identified the blood-derived protein fibrinogen as a key molecule regulating the differentiation of subventricular zone-derived adult neural stem cells into astrocytes in areas of cortical brain damage with vascular leakage.Neural stem/progenitor cells (NSPCs) of the adult subventricular zone (SVZ) continuously generate migrating DCX+ neuroblasts integrating into the olfactory bulb circuitry within the healthy brain. In CNS disease a considerable proportion of SVZ-derived NSPCs change their migration path to the lesion area and mainly differentiate into astrocytes at the expense of neuronal differentiation. NSPC lineage fate is controlled by a fine tuned microenvironment, which dramatically changes after brain trauma due to blood brain-barrier (BBB) disruption with subsequent hemorrhage. Here, we show that blood-derived fibrinogen, which is deposited in the NSPC environment upon brain injury with vascular rupture, regulates NSPC differentiation into astrocytes via activation of the BMP receptor signaling pathway. Genetic elimination of fibrinogen reduces the number of newborn SVZ-derived astrocytes in the lesion area after cortical injury. Furthermore, stereotactic injection of fibrinogen into the mouse cortex is sufficient to induce the differentiation of NSPCs into astrocytes. Fibrinogen represses the expression of cell cycle associated genes and induces the expression of BMP signaling target genes. Inhibition of the BMP receptor pathway abolishes fibrinogen-induced NSPC differentiation into astrocytes in vitro. Consequently, fibrinogen depletion with anticoagulant treatment leads to increased neurogenesis in the lesion area after cortical injury. Thus, the presence of fibrinogen in the CNS after vascular rupture changes the NSPC environment and promotes the differentiation of NSPCs into astrocytes by engaging BMP receptor signaling.
