Aging-enhanced accumulation of fibroblasts excludes oligodendrocytes in demyelinated lesions

Abstract

Fibroblast dysregulation contributes to aberrant repair and pathological fibrosis. Emerging evidence suggest that fibroblasts accumulate in lesions following central nervous system injury, but whether and how they influence oligodendrocytes and myeloid cell responses, especially in aging, is uncertain. Here we report that fibroblasts infiltrate the parenchyma of spinal cord white matter (SCWM) lesions after lysolecithin-induced demyelination. Transcriptomic analysis reveals diverse activation states of fibroblasts in lesions and communication networks between fibroblasts, microglia/macrophages and oligodendrocyte precursor cells (OPCs). The invasion of fibroblasts is facilitated by microglia/macrophages, and areas of fibroblast accumulation are devoid of OPCs. Fibroblast density is exacerbated with aging leading to greater fibrosis in lesions. Finally, we found fibroblasts in multiple sclerosis lesions with predicted communication networks between microglia/macrophages and OPCs. These results demonstrate a role of fibroblasts in demyelination-associated neuropathology, which is exacerbated by aging, and highlight the importance of regulating fibroblasts to promote effective CNS repair.