DOI: 10.1002/ame2.70009
Transplanting neural stem cells overexpressing miRNA-21 can promote neural recovery after cerebral hemorrhage through the SOX2/LIN28-let-7 signaling pathway
Wei Dai
Yongxia Li
Jiarui Du
Gang Shen
Meimei Fan
Zuopeng Su
Fulin Xu
Fang Yuan
Abstract：Background: Intracerebral 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.
Methods: In 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).
Results: miR-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.
Conclusions: Our 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.
Keywords：intracerebral hemorrhage(ICH)LIN28-let7miRNA-21neural stem cells(NSCs)SOX2
Publication Date：2025-10-30
Online Publishing Date：2025-12-16(First online date of this platform, not the publication date of the document)
Pages：15( 1760-1774 )