The Origin and Function of CNS Fibrosis
- Author(s): Dorrier, Cayce
- Advisor(s): Daneman, Richard
- et al.
Fibrosis is a common pathological response to inflammation in many peripheral tissues and can prevent tissue regeneration and repair. Despite the potential importance, very little is known about the fibrotic response in the central nervous system (CNS), and how this may impact the regenerative process. We identified persistent fibrotic scarring in the brain and spinal cord following neuroinflammation. Using lineage tracing and single-cell sequencing in the EAE mouse model of multiple sclerosis, we determined that this fibrotic scar is derived from proliferative CNS resident fibroblasts, not pericytes or infiltrating bone marrow-derived cells. Ablating proliferating fibroblasts using the fibroblast-specific expression of herpes thymidine kinase led to an increase in oligodendrocyte lineage cells within inflammatory lesions and a reduction in motor disability. We further identified that interferon gamma pathway genes are enriched in CNS fibroblasts, and the fibroblast-specific deletion of Ifngr1 resulted in a reduced fibrotic scar in EAE. Additionally, we identified that platelet derived growth factor receptor signaling affects brain fibroblast development and fibroblast migration. In the retina, fibrosis occurs following retinopathies and can lead to retinal detachment and blindness, and yet little is known about the origin of this fibrosis as it has been difficult to model in mice. We generated a novel mouse model of oxygen-induced retinopathies that exhibits persistent fibrotic pathology, and used histology and single-cell sequencing to determine that the origin of the fibrotic scar in the retina is likely pericytes. These data delineate a framework for understanding CNS fibrosis.