Aging-enhanced accumulation of fibroblasts excludes oligodendrocytes in demyelinated lesions.
8 affiliations
- 1Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
- 2Department of Biology, Georgetown University, Washington, DC, USA.
- 3Department of Immunology, University of British Columbia, Vancouver, Canada.
- 4Department of Biology, University of Toronto Mississauga, Mississauga, Canada.
- 5Department of Chemistry, University of Calgary, Calgary, Canada.
- 6Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
- 7Department of Biology, Georgetown University, Washington, DC, USA. [email protected].
- 8Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, Canada. [email protected].
Abstract
Fibroblast dysregulation contributes to pathological fibrosis and aberrant repair. Emerging evidence suggest that fibroblasts accumulate in lesions following central nervous system injury, but whether and how they influence oligodendrocyte repair responses, including in aging, is uncertain. Here we report that fibroblasts accumulate in the parenchyma of spinal cord white matter lesions of 6 - 10 week old young mice after lysolecithin-induced demyelination. This was first observed through immunofluorescence microscopy that employed several markers attributed to fibroblasts, including platelet-derived growth factor-β, collagen type 1α1, α-smooth muscle actin, periostin and fibronectin; and by the use of platelet-derived growth factor-β TdTomato reporter transgenic mice. Single-nucleus and spatial transcriptomics of lysolecithin lesions established the presence of fibroblasts in lysolecithin lesions and delineated them from closely related pericytes. CellChat ligand - receptor analyses highlight fibroblasts in the lysolecithin environment as a major source of input of signals for microglia/macrophages and oligodendrocyte precursor cells, with numerous reciprocal interactions. The infiltration of fibroblasts was promoted by microglia/macrophages, as anticipated by their temporal representation in lysolecithin lesions, and by tissue culture experiments where the migration of fibroblasts was enhanced by macrophages. Of particular relevance to spontaneous regenerative events in lysolecithin demyelination, areas of fibroblast accumulation were devoid of oligodendrocyte precursor cells. In tissue culture, oligodendrocyte precursor cells were excluded from fibroblast domains. Moreover, fibroblast accumulation after lysolecithin injury was enhanced with increasing age, a known detriment to the capacity to remyelinate after injury, and exclusion of oligodendrocyte precursor cells from fibroblast areas of 48-52 week mice exceeds that occurring in younger 6-10 weeks animals. Finally, by mining a publicly available single-nucleus RNA database of multiple sclerosis, we found fibroblasts in the edge of chronic active and chronic inactive lesions and in lesion core, and fewer in periplaque or normal white matter. We identified several communication networks between fibroblasts, microglia/macrophages and oligodendrocyte precursor cells in these MS lesions. Our collective 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.
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BibTeX
@article{lozinski2026agingenhanced,
title = {{Aging-enhanced accumulation of fibroblasts excludes oligodendrocytes in demyelinated lesions.}},
author = {Brian M Lozinski and George S Melchor and Charlotte D'Mello and Rianne P Gorter and Yifei Dong and Samira Ghorbani and Cenxiao Li and Marlene Morch and Dorsa Moezzi and Rajiv Jain and Parisa Etemadi Nezhad and Chang-Chun Ling and Carlos Camara-Lemarroy and Rui Li and Jeffrey K Huang and V Wee Yong},
journal = {Journal of neuroinflammation},
year = {2026},
month = jul,
doi = {10.1186/s12974-026-03976-z},
url = {https://europepmc.org/article/MED/42902401},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Aging-enhanced accumulation of fibroblasts excludes oligodendrocytes in demyelinated lesions.
AU - Brian M Lozinski
AU - George S Melchor
AU - Charlotte D'Mello
AU - Rianne P Gorter
AU - Yifei Dong
AU - Samira Ghorbani
AU - Cenxiao Li
AU - Marlene Morch
AU - Dorsa Moezzi
AU - Rajiv Jain
AU - Parisa Etemadi Nezhad
AU - Chang-Chun Ling
AU - Carlos Camara-Lemarroy
AU - Rui Li
AU - Jeffrey K Huang
AU - V Wee Yong
PY - 2026
DA - 2026/07/01
JO - Journal of neuroinflammation
DO - 10.1186/s12974-026-03976-z
UR - https://europepmc.org/article/MED/42902401
AB - Fibroblast dysregulation contributes to pathological fibrosis and aberrant repair. Emerging evidence suggest that fibroblasts accumulate in lesions following central nervous system injury, but whether and how they influence oligodendrocyte repair responses, including in aging, is uncertain. Here we report that fibroblasts accumulate in the parenchyma of spinal cord white matter lesions of 6 - 10 week old young mice after lysolecithin-induced demyelination. This was first observed through immunofluorescence microscopy that employed several markers attributed to fibroblasts, including platelet-derived growth factor-β, collagen type 1α1, α-smooth muscle actin, periostin and fibronectin; and by the use of platelet-derived growth factor-β TdTomato reporter transgenic mice. Single-nucleus and spatial transcriptomics of lysolecithin lesions established the presence of fibroblasts in lysolecithin lesions and delineated them from closely related pericytes. CellChat ligand - receptor analyses highlight fibroblasts in the lysolecithin environment as a major source of input of signals for microglia/macrophages and oligodendrocyte precursor cells, with numerous reciprocal interactions. The infiltration of fibroblasts was promoted by microglia/macrophages, as anticipated by their temporal representation in lysolecithin lesions, and by tissue culture experiments where the migration of fibroblasts was enhanced by macrophages. Of particular relevance to spontaneous regenerative events in lysolecithin demyelination, areas of fibroblast accumulation were devoid of oligodendrocyte precursor cells. In tissue culture, oligodendrocyte precursor cells were excluded from fibroblast domains. Moreover, fibroblast accumulation after lysolecithin injury was enhanced with increasing age, a known detriment to the capacity to remyelinate after injury, and exclusion of oligodendrocyte precursor cells from fibroblast areas of 48-52 week mice exceeds that occurring in younger 6-10 weeks animals. Finally, by mining a publicly available single-nucleus RNA database of multiple sclerosis, we found fibroblasts in the edge of chronic active and chronic inactive lesions and in lesion core, and fewer in periplaque or normal white matter. We identified several communication networks between fibroblasts, microglia/macrophages and oligodendrocyte precursor cells in these MS lesions. Our collective 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.
SN - 1742-2094
ER -