Neural stem cells(NSCs)have the potential for self-renewal and multidirectional differentiation,and their transplantation has achieved good efficacy in a variety of diseases.However,only 1%-10%of transplanted NSCs sur...Neural stem cells(NSCs)have the potential for self-renewal and multidirectional differentiation,and their transplantation has achieved good efficacy in a variety of diseases.However,only 1%-10%of transplanted NSCs survive in the ischemic and hypoxic microenvironment of posthemorrhagic hydrocephalus.^(Sox2)is an important factor for NSCs to maintain proliferation.Therefore,^(Sox2)-overexpressing NSCs(NSC^(Sox2))may be more successful in improving neurological dysfunction after posthemorrhagic hydrocephalus.In this study,human NSC^(Sox2)was transplanted into a posthemorrhagic hydrocephalus mouse model,and retinoic acid was administered to further promote NSC differentiation.The results showed that NSC^(Sox2)attenuated the ventricular enlargement caused by posthemorrhagic hydrocephalus and improved neurological function.NSC^(Sox2)also promoted nerve regeneration,inhibited neuroinflammation and promoted M2 polarization(anti-inflammatory phenotype),thereby reducing cerebrospinal fluid secretion in choroid plexus.These findings suggest that NSC^(Sox2)rescued ventricular enlargement and neurological dysfunction induced by posthemorrhagic hydrocephalus through neural regeneration and modulation of inflammation.展开更多
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supported by the National Natural Science Foundation of China,Nos.82473334(to LZ),82401629(to XL)the Major Scientific and Technological Achievements Transformation Project of Ningxia Hui Autonomous Region,No.2022CJE09013(to LZ)+4 种基金Mianyang Science and Technology Bureau(Mianyang Science and Technology Program),No.2023ZYDF097(to LZ)NHC Key Laboratory of Nuclear Technology Medical Transformation(Mianyang Central Hospital),No.2023HYX001(to LZ)Spinal Cord Diseases Clinical Medical Center of Yunnan Province,No.2024JSKFKT-16(to BG)the Natural Science Foundation of Sichuan Province,No.2024NSFSC1646(to XL)the China Postdoctoral Science Foundation,Nos.GZC20231811(to XL),2024T170601(to XL)and 2024M76228(to XL).
文摘Neural stem cells(NSCs)have the potential for self-renewal and multidirectional differentiation,and their transplantation has achieved good efficacy in a variety of diseases.However,only 1%-10%of transplanted NSCs survive in the ischemic and hypoxic microenvironment of posthemorrhagic hydrocephalus.^(Sox2)is an important factor for NSCs to maintain proliferation.Therefore,^(Sox2)-overexpressing NSCs(NSC^(Sox2))may be more successful in improving neurological dysfunction after posthemorrhagic hydrocephalus.In this study,human NSC^(Sox2)was transplanted into a posthemorrhagic hydrocephalus mouse model,and retinoic acid was administered to further promote NSC differentiation.The results showed that NSC^(Sox2)attenuated the ventricular enlargement caused by posthemorrhagic hydrocephalus and improved neurological function.NSC^(Sox2)also promoted nerve regeneration,inhibited neuroinflammation and promoted M2 polarization(anti-inflammatory phenotype),thereby reducing cerebrospinal fluid secretion in choroid plexus.These findings suggest that NSC^(Sox2)rescued ventricular enlargement and neurological dysfunction induced by posthemorrhagic hydrocephalus through neural regeneration and modulation of inflammation.
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.
