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
近来认为鼻咽癌干细胞的存在是导致放射抵抗最重要的原因。Lin28是一种原癌基因,通过选择性阻断Let-7 mi RNA家族成员的加工合成,阻碍mi RNA对原癌基因的抑制作用。同时又与RNA解旋酶相互作用,增强基因翻译,并且Let-7对Lin28和C-myc起...近来认为鼻咽癌干细胞的存在是导致放射抵抗最重要的原因。Lin28是一种原癌基因,通过选择性阻断Let-7 mi RNA家族成员的加工合成,阻碍mi RNA对原癌基因的抑制作用。同时又与RNA解旋酶相互作用,增强基因翻译,并且Let-7对Lin28和C-myc起反馈抑制调节作用。C-myc调控DNA损伤检验点反应,引起鼻咽癌干细胞的放疗耐受性,我们回顾性分析相关文献,探讨Lin28/Let-7/C-myc调节环与鼻咽癌干细胞的靶向治疗关系的研究进展。展开更多
let-7 mi RNA家族控制许多决定细胞命运的基因的表达,从而影响细胞的多能性、分化和转化.Lin28是一个let-7生物合成的转录后抑制因子,其碳端的锌指结构域特异性地结合一个保守的GGAG或者一个类似GGAG的let-7 mi RNA模块.作者报道了人源L...let-7 mi RNA家族控制许多决定细胞命运的基因的表达,从而影响细胞的多能性、分化和转化.Lin28是一个let-7生物合成的转录后抑制因子,其碳端的锌指结构域特异性地结合一个保守的GGAG或者一个类似GGAG的let-7 mi RNA模块.作者报道了人源Lin28与5′-A–2A–1G1G2A3G4-3′let-7 RNA复合物的核磁共振结构.Lin28中两个Lin28 ZKD识别了RNA中的G1G2A3G4.复合物所有的碱基采取反式构象,RNA的骨架因为Lin28的结合变得弯曲,与之前报道的晶体结构一致而与NMR结构不同,从而进一步确认了Lin28识别RNA的作用模式.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.
文摘近来认为鼻咽癌干细胞的存在是导致放射抵抗最重要的原因。Lin28是一种原癌基因,通过选择性阻断Let-7 mi RNA家族成员的加工合成,阻碍mi RNA对原癌基因的抑制作用。同时又与RNA解旋酶相互作用,增强基因翻译,并且Let-7对Lin28和C-myc起反馈抑制调节作用。C-myc调控DNA损伤检验点反应,引起鼻咽癌干细胞的放疗耐受性,我们回顾性分析相关文献,探讨Lin28/Let-7/C-myc调节环与鼻咽癌干细胞的靶向治疗关系的研究进展。
基金Grants from the Ministry of Science and Technology of China(2011CB966300)the National Natural Science Foundation of China(21272261,21472229 and 21275154)the Science and Technology Commission of Shanghai Municipality(15ZR1449300)
文摘let-7 mi RNA家族控制许多决定细胞命运的基因的表达,从而影响细胞的多能性、分化和转化.Lin28是一个let-7生物合成的转录后抑制因子,其碳端的锌指结构域特异性地结合一个保守的GGAG或者一个类似GGAG的let-7 mi RNA模块.作者报道了人源Lin28与5′-A–2A–1G1G2A3G4-3′let-7 RNA复合物的核磁共振结构.Lin28中两个Lin28 ZKD识别了RNA中的G1G2A3G4.复合物所有的碱基采取反式构象,RNA的骨架因为Lin28的结合变得弯曲,与之前报道的晶体结构一致而与NMR结构不同,从而进一步确认了Lin28识别RNA的作用模式.
