Newborn animals require tightly regulated local and systemic immune environments to govern the development and maturation of multiple organs/tissues even though the immune system itself is far from mature during the n...Newborn animals require tightly regulated local and systemic immune environments to govern the development and maturation of multiple organs/tissues even though the immune system itself is far from mature during the neonatal period.Regulatory T cells(Tregs)are essential for maintaining immune tolerance/homeostasis and modulating inflammatory responses.The features of Tregs in the neonatal liver under steady-state conditions are not well understood.The present study aimed to investigate the phenotype,functions,and significance of neonatal Tregs in the liver.We found a wave of thymus-derived Treg influx into the liver during 1–2 weeks of age.Depletion of these Tregs between days 7 and 11 after birth rapidly resulted in Th1-type liver inflammation and metabolic disorder.More Tregs in the neonatal liver than in the spleen underwent MHC II-dependent activation and proliferation,and the liver Tregs acquired stronger suppressive functions.The transcriptomic profile of these neonatal liver Tregs showed elevated expression of PPARγand T-bet and features of Tregs that utilize lipid metabolic machinery and are capable of regulating Th1 responses.The accumulation of Tregs with unique features in the neonatal liver is critical to ensure self-tolerance and liver maturation.展开更多
Aging associated cognitive decline has been linked to dampened neural stem/progenitor cells (NSC/NPCs) activities manifested by decreased proliferation, reduced propensity to produce neurons, and increased different...Aging associated cognitive decline has been linked to dampened neural stem/progenitor cells (NSC/NPCs) activities manifested by decreased proliferation, reduced propensity to produce neurons, and increased differentiation into astrocytes. While gene transcription changes objectively reveal molecular alterations of cells undergoing various biological processes, the search for molecular mechanisms underlying aging of NSC/NPCs has been confronted by the enormous heterogeneity in cellular compositions of the brain and the complex cellular microenvironment where NSC/NPCs reside. Moreover, brain NSClNPCs themselves are not a homogenous population, making it even more difficult to uncover NSC/NPC sub-type specific aging mechanisms. Here, using both population-based and single cell transcriptome analyses of young and aged mouse forebrain ependymal and subependymal regions and comprehensive "big-data" processing, we report that NSCINPCs reside in a rather inflammatory environment in aged brain, which likely contributes to the differentiation bias towards astrocytes versus neurons. Moreover, single cell transcriptome analyses revealed that different aged NSCINPC subpopulations, while all have reduced cell proliferation, use different gene transcription programs to regulate age-dependent decline in cell cycle. Inter- estingly, changes in cell proliferation capacity are not influenced by inflammatory cytokines, but likely result from cell intrinsic mechanisms. The ErkJMapk pathway appears to be critically involved in regulating age-dependent changes in the capacity for NSCINPCs to undergo clonal expansion. Together this study is the first example of using population and single cell based transcriptome analyses to unveil the molecular interplay between different NSCINPCs and their microenvironment in the context of the aging brain.展开更多
Spinal cord injury(SCI)involves diverse injury responses in different cell types in a temporally and spatially specific manner.Here,using single-cell transcriptomic analyses combined with classic anatomical,behavioral...Spinal cord injury(SCI)involves diverse injury responses in different cell types in a temporally and spatially specific manner.Here,using single-cell transcriptomic analyses combined with classic anatomical,behavioral,electrophysiological analyses,we report,with single-cell resolution,temporal molecular and cellular changes in crush-injured adult mouse spinal cord.Data revealed pathological changes of 12 different major cell types,three of which infiltrated into the spinal cord at distinct times post-injury.We discovered novel microglia and astrocyte subtypes in the uninjured spinal cord,and their dynamic conversions into additional stage-specific subtypes/states.Most dynamic changes occur at 3-days post-injury and by day-14 the second wave of microglial activation emerged,accompanied with changes in various cell types including neurons,indicative of the second round of attacks.By day-38,major cell types are still substantially deviated from uninjured states,demonstrating prolonged alterations.This study provides a comprehensive mapping of cellular/molecular pathological changes along the temporal axis after SCI,which may facilitate the development of novel therapeutic strategies,including those targeting microglia.展开更多
The mammalian brain is heterogeneous, containing billions of neurons and trillions of synapses forming vari- ous neural circuitries, through which sense, movement, thought, and emotion arise. The cellular heterogeneit...The mammalian brain is heterogeneous, containing billions of neurons and trillions of synapses forming vari- ous neural circuitries, through which sense, movement, thought, and emotion arise. The cellular heterogeneity of the brain has made it difficult to study the molecular logic of neural circuitry wiring, pruning, activation, and plasticity, until recently, transcriptome analyses with single cell resolution makes decoding of gene regulatory networks underlying aforementioned circuitry properties possible. Here we report success in per- forming both electrophysiological and whole-genome transcriptome analyses on single human neurons in culture. Using Weighted Gene Coexpression Network Analyses (WGCNA), we identified gene clusters highly correlated with neuronal maturation judged by electrophysiological characteristics. A tight link between neu- ronal maturation and genes involved in ubiquitination and mitochondrial function was revealed. Moreover, we identified a list of candidate genes, which could potentially serve as biomarkers for neuronal maturation. Coupled electrophysiological recording and single cell transcriptome analysis will serve as powerful tools in the future to unveil molecular logics for neural circuitry functions.展开更多
基金by grants from the National Key Research and Development Program of China(2017YFA0104500)the National Natural Science Foundation of China(81471525,31671244,and 31872734,Q.G.+2 种基金81601975,K.Z.)the Foundation for Innovative Research Groups of the National Natural Science Foundation of China(81621001)the Non-Profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2018PT31039).
文摘Newborn animals require tightly regulated local and systemic immune environments to govern the development and maturation of multiple organs/tissues even though the immune system itself is far from mature during the neonatal period.Regulatory T cells(Tregs)are essential for maintaining immune tolerance/homeostasis and modulating inflammatory responses.The features of Tregs in the neonatal liver under steady-state conditions are not well understood.The present study aimed to investigate the phenotype,functions,and significance of neonatal Tregs in the liver.We found a wave of thymus-derived Treg influx into the liver during 1–2 weeks of age.Depletion of these Tregs between days 7 and 11 after birth rapidly resulted in Th1-type liver inflammation and metabolic disorder.More Tregs in the neonatal liver than in the spleen underwent MHC II-dependent activation and proliferation,and the liver Tregs acquired stronger suppressive functions.The transcriptomic profile of these neonatal liver Tregs showed elevated expression of PPARγand T-bet and features of Tregs that utilize lipid metabolic machinery and are capable of regulating Th1 responses.The accumulation of Tregs with unique features in the neonatal liver is critical to ensure self-tolerance and liver maturation.
基金This study was supported by China National Key Research and Development Program (2016YFA0100801 YS), and the National Natural Science Foundation of China (Grant Nos. 8133030 YS and 31620103904 YS), and grants: 2016YFC102705 YS 2014BAI04B07 WZL+1 种基金 81470715 YSTJ1504219036 WZL.
文摘Aging associated cognitive decline has been linked to dampened neural stem/progenitor cells (NSC/NPCs) activities manifested by decreased proliferation, reduced propensity to produce neurons, and increased differentiation into astrocytes. While gene transcription changes objectively reveal molecular alterations of cells undergoing various biological processes, the search for molecular mechanisms underlying aging of NSC/NPCs has been confronted by the enormous heterogeneity in cellular compositions of the brain and the complex cellular microenvironment where NSC/NPCs reside. Moreover, brain NSClNPCs themselves are not a homogenous population, making it even more difficult to uncover NSC/NPC sub-type specific aging mechanisms. Here, using both population-based and single cell transcriptome analyses of young and aged mouse forebrain ependymal and subependymal regions and comprehensive "big-data" processing, we report that NSCINPCs reside in a rather inflammatory environment in aged brain, which likely contributes to the differentiation bias towards astrocytes versus neurons. Moreover, single cell transcriptome analyses revealed that different aged NSCINPC subpopulations, while all have reduced cell proliferation, use different gene transcription programs to regulate age-dependent decline in cell cycle. Inter- estingly, changes in cell proliferation capacity are not influenced by inflammatory cytokines, but likely result from cell intrinsic mechanisms. The ErkJMapk pathway appears to be critically involved in regulating age-dependent changes in the capacity for NSCINPCs to undergo clonal expansion. Together this study is the first example of using population and single cell based transcriptome analyses to unveil the molecular interplay between different NSCINPCs and their microenvironment in the context of the aging brain.
基金grants from the National Key Research and Development Program of China(No.2016YFA0100800)the International(regional)cooperation and communication program of the National Natural Science Foundation of China(No.81820108013,31620103904,82030035)the State Key Program of the National Natural Science Foundation of China(No.81330030).
文摘Spinal cord injury(SCI)involves diverse injury responses in different cell types in a temporally and spatially specific manner.Here,using single-cell transcriptomic analyses combined with classic anatomical,behavioral,electrophysiological analyses,we report,with single-cell resolution,temporal molecular and cellular changes in crush-injured adult mouse spinal cord.Data revealed pathological changes of 12 different major cell types,three of which infiltrated into the spinal cord at distinct times post-injury.We discovered novel microglia and astrocyte subtypes in the uninjured spinal cord,and their dynamic conversions into additional stage-specific subtypes/states.Most dynamic changes occur at 3-days post-injury and by day-14 the second wave of microglial activation emerged,accompanied with changes in various cell types including neurons,indicative of the second round of attacks.By day-38,major cell types are still substantially deviated from uninjured states,demonstrating prolonged alterations.This study provides a comprehensive mapping of cellular/molecular pathological changes along the temporal axis after SCI,which may facilitate the development of novel therapeutic strategies,including those targeting microglia.
基金The online version of this article (doi:10.1007/s13238-016-0247-8) contains supplementary material, which is available to authorized users.This work was supported by the National Basic Research Program (973 Program) (No. 2012CB966303), the National Natural Science Foundation of China (Grant Nos. 81330030, 91319309, and 31271371), the Science and Technology Department of Yunnan Province (Grant 2012HA013), the Yunnan Basic Research Projects (Grant 2014FC004), and the Doctoral Tutor of Education Department of Shanghai, China (Grant 20130072110021 ), grants from NASAD: BRN & BEHV RES FND 23072, NIH R21:IR21NS095184-01 and finally, a fellowship from China Scholarship Council to X. -Y.C.
文摘The mammalian brain is heterogeneous, containing billions of neurons and trillions of synapses forming vari- ous neural circuitries, through which sense, movement, thought, and emotion arise. The cellular heterogeneity of the brain has made it difficult to study the molecular logic of neural circuitry wiring, pruning, activation, and plasticity, until recently, transcriptome analyses with single cell resolution makes decoding of gene regulatory networks underlying aforementioned circuitry properties possible. Here we report success in per- forming both electrophysiological and whole-genome transcriptome analyses on single human neurons in culture. Using Weighted Gene Coexpression Network Analyses (WGCNA), we identified gene clusters highly correlated with neuronal maturation judged by electrophysiological characteristics. A tight link between neu- ronal maturation and genes involved in ubiquitination and mitochondrial function was revealed. Moreover, we identified a list of candidate genes, which could potentially serve as biomarkers for neuronal maturation. Coupled electrophysiological recording and single cell transcriptome analysis will serve as powerful tools in the future to unveil molecular logics for neural circuitry functions.