Transplanting neural stem cells overexpressing miRNA‐21 can promote neural recovery after cerebral hemorrhage through the SOX2/LIN28‐let‐7 signaling pathway

• DOI: 10.1002/ame2.70009
• Publication Date: 2025-03-12T10:29:18Z
• Authors: Wei Dai; Yongxia Li; Jiarui Du; Gang Shen; Meimei Fan; Zuopeng Su; Fulin Xu; Fang Yuan

AbstractBackgroundIntracerebral hemorrhage (ICH) remains a devastating neurological disorder with limited therapeutic options. Neural stem cell (NSC)‐based therapies have emerged as a potential regenerative approach, yet the molecular mechanisms regulating NSC behavior require further elucidation. The role of miR‐21 in NSC differentiation and proliferation during ICH recovery remains unexplored.MethodsIn vitro NSC cultures were analyzed for miR‐21 expression dynamics during differentiation via qPCR. Lentiviral overexpression and knockdown of miR‐21 were employed to assess its functional impact. The SOX2/LIN28‐let‐7 pathway was investigated using Western blot, luciferase reporter assays, and immunofluorescence. In vivo, miR‐21‐overexpressing NSCs were transplanted into a murine ICH model, with neurogenesis evaluated by immunostaining and neurological recovery assessed through behavioral tests (mNSS, rotarod).ResultsmiR‐21 expression significantly increased during NSC differentiation, correlating with reduced SOX2 levels. Mechanistically, miR‐21 directly targeted SOX2, disrupting the SOX2/LIN28‐let‐7 axis to promote NSC proliferation and lineage commitment. In ICH mice, transplantation of miR‐21‐overexpressing NSCs enhanced neurogenesis and improved motor coordination and neurological deficits at 28 days post‐transplantation.ConclusionsOur findings identify miR‐21 as a critical regulator of NSC plasticity through SOX2/LIN28‐let‐7 signaling, highlighting its therapeutic potential for enhancing neuroregeneration and functional recovery in ICH. Targeting miR‐21 may represent a novel strategy to optimize NSC‐based therapies for hemorrhagic stroke.