Age-Dependent Fibroblast Programs Govern Regenerative and Fibrotic Tendon Repair

Pazarceviren, A.; Bastani, M.; Roell, D.; Sheyn, J.; Huang, D.; Shelest, O.; Orr, M.; Zila, L.; Metzger, M.; Tawackoli, W.; Sheyn, D.

doi:10.64898/2026.07.22.739917

bioRxiv · 10.64898/2026.07.22.739917

Age-Dependent Fibroblast Programs Govern Regenerative and Fibrotic Tendon Repair

Pazarceviren, A.·Bastani, M.·Roell, D.·Sheyn, J.·Huang, D.·Shelest, O.·Orr, M.·Zila, L.·Metzger, M.·Tawackoli, W.·Sheyn, D.

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Abstract

Tendon injuries often result in fibrosis, compromising function and predisposing to re-injury. Here, we used a full-width, non-repair Achilles tendon transection model in young (3 weeks old) and adult (18-20 weeks) rats to elucidate the cellular mechanisms governing regenerative versus fibrotic healing. Functional and biomechanical analyses revealed that young tendons recovered motion and load-bearing capacity more rapidly but exhibited more fibrotic early healing. Single-nuclei RNA sequencing identified seven major cell populations within the connective tissue compartment. Adult tendons maintained a "synthetic fibroblast" population marked by upregulated ECM synthesis, reduced stress-related gene expression, whereas young tendons favored expansion of Cxcl12/Lrp6/Gas6 fibrotic fibroblasts linked to oxidative and pro-angiogenic signaling. The young group showed sustained activation of Nox4-Gas6 pathways driving a self-reinforcing fibrotic circuit. These findings define a fibroblast lineage bifurcation that dictates oxidative stress signaling as a key regulator of fibrotic remodeling, highlighting potential therapeutic targets to promote regenerative tendon repair.

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Pazarceviren, A., Bastani, M., Roell, D., Sheyn, J., Huang, D., Shelest, O., Orr, M., Zila, L., Metzger, M., Tawackoli, W., Sheyn, D.. 2026-07-26. Age-Dependent Fibroblast Programs Govern Regenerative and Fibrotic Tendon Repair. https://doi.org/10.64898/2026.07.22.739917

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