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 mole...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.展开更多
基金Shanghai Minhang District Health Commission Project,Grant/Award Number:2022MHZ062Shanghai Sixth People's Hospital,Grant/Award Number:ynhg202311 and ynms202411。
文摘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.
