CNS Neuroscience & Therapeutics · Jul 29, 2026

hUC-MSCs via β-NGF Alleviate Cognitive Impairment After Tibial Fracture Surgery by Regulating the STMN2/NMNAT2-SARM1-NF-κB Signaling Pathway

By Wang K, Wang F, Zhang Y et al.

BACKGROUND: Perioperative neurocognitive disorders (PND) are common postoperative complications, particularly in elderly patients, marked by learning and memory deficits with limited treatment options. Human umbilical cord mesenchymal stem cells (hUC-MSCs) hold promise due to their neuroprotective and immunomodulatory effects, but their underlying mechanisms remain unclear. METHODS: This study established a PND model in aged mice using tibial fracture intramedullary fixation surgery, followed by intravenous hUC-MSCs administration. Subsequently, behavioral tests, pathological examination, proteomic analysis, and other experiments were performed to verify the therapeutic effect and underlying mechanism of hUC-MSCs on PND in mice. RESULTS: hUC-MSCs significantly improved cognitive function in PND mice, reduced hippocampal neuronal apoptosis and neuroinflammation, and restored dendritic spine density. Mechanistically, hUC-MSCs secreted β-NGF to activate the TrkA signaling pathway, upregulate STMN2 and NMNAT2 expression, and inhibit the SARM1/NF-κB pathway, thereby alleviating neuroinflammation and dendritic degeneration. Overexpression of SARM1 in the hippocampal CA1 region and β-NGF knockdown in hUC-MSCs both reversed the therapeutic effects of hUC-MSCs, confirming their critical roles. CONCLUSIONS: hUC-MSCs ameliorate PND pathology through the β-NGF-mediated STMN2/NMNAT2-SARM1-NF-κB pathway, offering a novel cell-based therapeutic strategy for PND. Future research may focus on optimizing the secretory function of hUC-MSCs or developing small-molecule drugs targeting β-NGF to enhance therapeutic efficacy.

doi.org/10.1002/cns.71062 Open access PubMed 42524858 Interventions