Chaoqun Yao, Long Jin, Jun Zhong, Qianying Huang, Zhongwei Bao, Shaolong Zhou, Chaohua Wang, Huanhuan Li, Xiaowei Yuan, Zhen Wang, Ning Du, Jingxuan Yu, Huanran Chen, Xuyang Zhang, Hongfei Ge, Jianheng Wu
{"title":"创伤性脑损伤后rho相关卷曲蛋白激酶1的失调消耗神经干细胞库并损害海马神经发生","authors":"Chaoqun Yao, Long Jin, Jun Zhong, Qianying Huang, Zhongwei Bao, Shaolong Zhou, Chaohua Wang, Huanhuan Li, Xiaowei Yuan, Zhen Wang, Ning Du, Jingxuan Yu, Huanran Chen, Xuyang Zhang, Hongfei Ge, Jianheng Wu","doi":"10.1111/cpr.70093","DOIUrl":null,"url":null,"abstract":"<p><p>Traumatic brain injury (TBI) represents a global health burden, often resulting in persistent neurological deficits due to impaired hippocampal neurogenesis. Nevertheless, the temporal progression of post-TBI neurogenesis and its molecular mechanisms remain elusive. To investigate the mechanism of impaired hippocampal neurogenesis and neurological deficits following TBI. Single-cell RNA sequencing (scRNA-seq) was employed to explore the mechanism of abnormal hippocampal neurogenesis after TBI in mice. Antagonists and conditional gene knockout (CKO) strategies were applied to dissect the molecular function of target genes. Here, we found that neural stem cells (NSCs) were hyperactivated as observed in Nestin-GFP reporter mice in hippocampus during the early phases of TBI, followed by progressive depletion of the NSC pool, impaired neurogenesis, and the onset of progressive cognitive dysfunction. ScRNA-seq transcriptomic analysis revealed sustained upregulation of Rho-associated coiled-coil protein kinase 1 (ROCK1) in hippocampal NSCs post-TBI. Pharmacological inhibition of ROCK1 or ROCK1 CKO rescued chronic neurogenic deficits and improved cognitive functions in TBI mice. Mechanistically, ROCK1 dysregulation impaired neurogenesis via aberrant AKT hyperphosphorylation, establishing a unidirectional ROCK1-AKT signalling axis in adult hippocampal neurogenesis. Our findings position ROCK1 as a pivotal regulator of the post-TBI NSC pool hyperactivation and aberrant neurogenesis and propose targeted kinase inhibition strategies as a potential therapy to mitigate abnormal neurogenesis in TBI patients.</p>","PeriodicalId":9760,"journal":{"name":"Cell Proliferation","volume":" ","pages":"e70093"},"PeriodicalIF":5.6000,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dysregulation of Rho-Associated Coiled-Coil Protein Kinase1 Depletes Neural Stem Cell Pool and Impairs Hippocampal Neurogenesis After Traumatic Brain Injury.\",\"authors\":\"Chaoqun Yao, Long Jin, Jun Zhong, Qianying Huang, Zhongwei Bao, Shaolong Zhou, Chaohua Wang, Huanhuan Li, Xiaowei Yuan, Zhen Wang, Ning Du, Jingxuan Yu, Huanran Chen, Xuyang Zhang, Hongfei Ge, Jianheng Wu\",\"doi\":\"10.1111/cpr.70093\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Traumatic brain injury (TBI) represents a global health burden, often resulting in persistent neurological deficits due to impaired hippocampal neurogenesis. Nevertheless, the temporal progression of post-TBI neurogenesis and its molecular mechanisms remain elusive. To investigate the mechanism of impaired hippocampal neurogenesis and neurological deficits following TBI. Single-cell RNA sequencing (scRNA-seq) was employed to explore the mechanism of abnormal hippocampal neurogenesis after TBI in mice. Antagonists and conditional gene knockout (CKO) strategies were applied to dissect the molecular function of target genes. Here, we found that neural stem cells (NSCs) were hyperactivated as observed in Nestin-GFP reporter mice in hippocampus during the early phases of TBI, followed by progressive depletion of the NSC pool, impaired neurogenesis, and the onset of progressive cognitive dysfunction. ScRNA-seq transcriptomic analysis revealed sustained upregulation of Rho-associated coiled-coil protein kinase 1 (ROCK1) in hippocampal NSCs post-TBI. Pharmacological inhibition of ROCK1 or ROCK1 CKO rescued chronic neurogenic deficits and improved cognitive functions in TBI mice. Mechanistically, ROCK1 dysregulation impaired neurogenesis via aberrant AKT hyperphosphorylation, establishing a unidirectional ROCK1-AKT signalling axis in adult hippocampal neurogenesis. Our findings position ROCK1 as a pivotal regulator of the post-TBI NSC pool hyperactivation and aberrant neurogenesis and propose targeted kinase inhibition strategies as a potential therapy to mitigate abnormal neurogenesis in TBI patients.</p>\",\"PeriodicalId\":9760,\"journal\":{\"name\":\"Cell Proliferation\",\"volume\":\" \",\"pages\":\"e70093\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell Proliferation\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1111/cpr.70093\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell Proliferation","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1111/cpr.70093","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Dysregulation of Rho-Associated Coiled-Coil Protein Kinase1 Depletes Neural Stem Cell Pool and Impairs Hippocampal Neurogenesis After Traumatic Brain Injury.
Traumatic brain injury (TBI) represents a global health burden, often resulting in persistent neurological deficits due to impaired hippocampal neurogenesis. Nevertheless, the temporal progression of post-TBI neurogenesis and its molecular mechanisms remain elusive. To investigate the mechanism of impaired hippocampal neurogenesis and neurological deficits following TBI. Single-cell RNA sequencing (scRNA-seq) was employed to explore the mechanism of abnormal hippocampal neurogenesis after TBI in mice. Antagonists and conditional gene knockout (CKO) strategies were applied to dissect the molecular function of target genes. Here, we found that neural stem cells (NSCs) were hyperactivated as observed in Nestin-GFP reporter mice in hippocampus during the early phases of TBI, followed by progressive depletion of the NSC pool, impaired neurogenesis, and the onset of progressive cognitive dysfunction. ScRNA-seq transcriptomic analysis revealed sustained upregulation of Rho-associated coiled-coil protein kinase 1 (ROCK1) in hippocampal NSCs post-TBI. Pharmacological inhibition of ROCK1 or ROCK1 CKO rescued chronic neurogenic deficits and improved cognitive functions in TBI mice. Mechanistically, ROCK1 dysregulation impaired neurogenesis via aberrant AKT hyperphosphorylation, establishing a unidirectional ROCK1-AKT signalling axis in adult hippocampal neurogenesis. Our findings position ROCK1 as a pivotal regulator of the post-TBI NSC pool hyperactivation and aberrant neurogenesis and propose targeted kinase inhibition strategies as a potential therapy to mitigate abnormal neurogenesis in TBI patients.
期刊介绍:
Cell Proliferation
Focus:
Devoted to studies into all aspects of cell proliferation and differentiation.
Covers normal and abnormal states.
Explores control systems and mechanisms at various levels: inter- and intracellular, molecular, and genetic.
Investigates modification by and interactions with chemical and physical agents.
Includes mathematical modeling and the development of new techniques.
Publication Content:
Original research papers
Invited review articles
Book reviews
Letters commenting on previously published papers and/or topics of general interest
By organizing the information in this manner, readers can quickly grasp the scope, focus, and publication content of Cell Proliferation.