Mesenchymal Stromal Cells Fuel Immunometabolic Reprogramming of Type 2 Conventional Dendritic Cells to Alleviate Systemic Sclerosis

Objective To investigate the clinical efficacy and underlying mechanisms of mesenchymal stromal cell (MSC) therapy in systemic sclerosis (SSc). Methods We prospectively evaluated the efficacy of MSC therapy in SSc patients. To elucidate the therapeutic mechanisms, we integrated paired multi‐omics data: proteomics (n=7), metabolomics (n=7), and both bulk (n=6) and single‐cell (n=2) RNA‐seq. Baseline disease‐associated signatures were mainly defined by publicly available datasets of peripheral blood mononuclear cells (PBMCs, 21 SSc vs. 6 healthy donors). Results MSC therapy significantly ameliorated skin fibrosis (median mRSS decrease 7.0 [IQR, 3.8–9.3], P < 0.05) and stabilized lung function after 6 months. In parallel with these clinical improvements, plasma proteomic analysis demonstrated that MSC therapy suppressed Hedgehog‐mediated fibrotic pathways ( P adj < 0.05). Transcriptomic profiling revealed that pathogenic type 2 conventional dendritic cells (cDC2s) exhibit intrinsic oxidative phosphorylation (OXPHOS) defects ( P adj < 0.05) in SSc. MSC therapy effectively repaired these defects and concurrently suppressed cDC2‐related inflammatory pathways in PBMCs and plasma ( P adj < 0.05). Consistent with these findings, single‐cell RNA‐seq revealed OXPHOS recovery in cDC2s alongside an increased proportion of homeostatic subsets. Conclusions Our study underscores the MSC‐mediated immunometabolic reprogramming to restore immune homeostasis by targeting upstream OXPHOS defects of cDC2s in SSc. image