Intravenous Human Umbilical Cord-Derived Mesenchymal Stromal Cells Promote Functional Recovery after Experimental Intracerebral Hemorrhage Via Local and Systemic Immunomodulation

Intracerebral hemorrhage (ICH) is associated with high mortality and disability, and current treatments offer limited benefits for functional recovery. Human umbilical cord-derived mesenchymal stromal cell (hUCMSC) have strong proliferative, neuroprotective, and immunomodulatory properties, making them attractive for clinical translation. We evaluated the therapeutic effects of intravenously administered hUCMSCs in a collagenase-induced ICH model using male mice. Mice received low or high doses of hUCMSC once or twice within 72 h after ICH. Repeated high-dose administration significantly improved motor, cognitive, and affective behaviors. Although repeated administration of high-dose hUCMSCs produced the most pronounced behavioral recovery, most subsequent analyses were performed using the single-dose groups. Histological analysis showed reduced neuronal apoptosis and microglial activation, consistent with neuroprotection. In vitro assays demonstrated suppression of inflammatory gene expression and promotion of an anti-inflammatory phenotype in immune cells. Flow cytometry revealed selective reduction of pro-inflammatory macrophages and microglia, increased reparative subsets, and systemic modulation of myeloid dynamics. Our results suggest that intravenous hUCMSC administration at a higher dose confers robust neuroprotection through coordinated local and systemic immunomodulation, providing translational insights for clinical MSC therapy in ICH.