Single-cell transcriptomics reveals that tenocyte-derived MIF contributes to tendon injury pathogenesis.

Tendon injury is accompanied by inflammation and pathological tissue remodeling, yet the underlying cellular and molecular mechanisms remain incompletely understood. Reanalysis of single-cell transcriptomic data across tendon-healing time points revealed dynamic cellular heterogeneity, including eight transcriptionally distinct mesenchymal subpopulations and eight immune-cell clusters. CellChat predicted relatively strong outgoing signaling from mesenchymal populations and incoming signaling to myeloid populations during repair. MIF-associated communication between selected tenocyte and myeloid populations was predicted to increase during the acute injury stage, involving the MIF-(CD74+CXCR4) and MIF-ACKR3 ligand-receptor pairs. MIF expression increased in injured tendon and was associated with inflammatory, apoptotic, stress-related, and histopathological changes. Pharmacological treatment with 4-IPP delivered in a photocrosslinked F127DA hydrogel formulation (F127@4-IPP) attenuated inflammation and osteogenic changes and improved histological outcomes in the mouse injury model. These findings support further evaluation of MIF-associated signaling and F127@4-IPP intervention in tendon injury.