Fibrinogen Mechanisms on Perivascular Fibroblast activation after Stroke

• Applicant: Professor Christian Schachtrup, Ph.D.
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 438640707

Scar formation is a common response to central nervous system (CNS) injury and disease and a major obstacle blocking CNS functional regeneration. The central non-neural “fibrotic” lesion core is composed of stromal cells, which are restricted to vascular and meningeal niches, and CNS-associated macrophages, including perivascular macrophages and peripherally derived macrophages, which together produce an excess of inhibitory extracellular matrix components, such as collagens. Previous work identified perivascular fibroblasts (PVF) as a novel source of the “fibrotic” non-neural lesion scar in CNS disease. Factors regulating fibrotic scar formation and, more specifically, PVF activation in CNS disease remain largely unknown. We identified an unexpected role for the blood-derived coagulation factor fibrinogen as a potential primary fibroblast activation signal, pointing to fibrinogen as a molecular link between vascular permeability and fibrotic scar formation. We will identify the effect of fibrinogen on PVF activation and migration affecting scar composition by utilizing pharmacologic and genetic tools to inhibit/deplete PVF cell surface receptors and to investigate the effect of fibrinogen-induced perivascular macrophage activation on PVF activation. We will determine the fibrinogen-induced changes in the molecular identity of PVF and their cross-communication with myeloid cells by single-cell RNA-Sequencing, RNAscope and immunohistochemical staining. Finally, we will manipulate fibrinogen-induced PVF activation towards improved brain repair and function. Overall, this study will enable us to pinpoint new molecular targets for the development of novel therapeutic approaches to promote functional recovery in stroke, which might then be applicable for other CNS injuries and diseases.

• DFG Programme: Research Grants