Single-cell atlas reveals age-related cellular shifts underlying fibrosis in murine synovium

Bortolotti, O.; Marineche, L.; Abasi-Ali, B.; Severac, D.; Leccia, F.; Duperray, C.; Brugioti, L.; Colinge, J.; Bertrand-Gaday, C.; Sebti, S.; Apparailly, F.; Courties, G.

doi:10.64898/2026.04.17.719179

bioRxiv · 10.64898/2026.04.17.719179

Single-cell atlas reveals age-related cellular shifts underlying fibrosis in murine synovium

Bortolotti, O.·Marineche, L.·Abasi-Ali, B.·Severac, D.·Leccia, F.·Duperray, C.·Brugioti, L.·Colinge, J.·Bertrand-Gaday, C.·Sebti, S.·Apparailly, F.·Courties, G.

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Abstract

Aging is a major risk factor for joint disease, yet the impact of physiological aging on the synovium remains poorly defined. Here we generate a single-cell atlas of murine ankle synovium across age and identify the sublining stromal-myeloid niche as a major site of age-associated remodeling. Aging shifted fibroblast states toward oxidative stress and matrix-remodeling programs, accompanied by sublining collagen accumulation, reduced cellularity, and loss of THY1+ sublining fibroblasts. In parallel, resident synovial macrophages exhibited altered inflammatory and phagocytic responses together with a preferential decline in TIM4+VSIG4- sublining macrophages, without overt local myeloid expansion despite systemic inflammaging. Macrophage depletion experiments further supported a link between sublining macrophages and extracellular matrix homeostasis. Together, these findings provide a reference framework for synovial aging and uncover niche-specific stromal and macrophage alterations associated with aging.

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Bortolotti, O., Marineche, L., Abasi-Ali, B., Severac, D., Leccia, F., Duperray, C., Brugioti, L., Colinge, J., Bertrand-Gaday, C., Sebti, S., Apparailly, F., Courties, G.. 2026-04-21. Single-cell atlas reveals age-related cellular shifts underlying fibrosis in murine synovium. https://doi.org/10.64898/2026.04.17.719179

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