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 central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influe...The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.展开更多
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National Key Basic Research Program from MOST, China (Nos. 2016YFA0100801 and 2014CB964602)the National Natural Science Foundation of China (Grant Nos. 81330030, 31620103904 and 81650110524)+1 种基金the National Institutes of Health (NIH5R21NS095184-02)the "RNAseq on Single Cell and beyond Core "in the Developme ntal Disabilities Research Center (NIH5U54HD087101-02) at University of California Los Angeles.
文摘The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.