The role of glial scar after intracerebral hemorrhage(ICH)remains unclear.This study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial...The role of glial scar after intracerebral hemorrhage(ICH)remains unclear.This study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar.We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation.Spatial transcriptomics(ST)analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods.During the early stage,sustained microglial depletion induced disorganized astrocytic scar,enhanced neutrophil infiltration,and impaired tissue repair.ST analysis indicated that microglia-derived insulin like growth factor 1(IGF1)modulated astrocytic scar formation via mechanistic target of rapamycin(mTOR)signaling activation.Moreover,repopulating microglia(RM)more strongly activated mTOR signaling,facilitating a more protective scar formation.The combination of IGF1 and osteopontin(OPN)was necessary and sufficient for RM function,rather than IGF1 or OPN alone.At the chronic stage of ICH,the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this.The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ICH.Inversely,early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy.This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes,and develop elaborate treatment strategies at precise time points after ICH.展开更多
Vasculature is the interface between tissue and circulation.It consists of endothelial cells,mural cells including vascular smooth muscle cells and pericytes,and other perivascular cells including macrophages and fibr...Vasculature is the interface between tissue and circulation.It consists of endothelial cells,mural cells including vascular smooth muscle cells and pericytes,and other perivascular cells including macrophages and fibroblasts(Sweeney et al.,2019).The vascular system not only delivers oxygen and nutrients,but also shuttles the immune cells around.As the first line of defense,the vascular system also senses the changes in surrounding tissue,particularly inflammation.Vascular inflammation can occur in blood vessels of all sizes in any organ.It has a complex etiology,including infections such as coronavirus disease-19(COVID-19),and chronic condi t ions such as diabetes,hypertension and neurodegenerative diseases(Hanafi et al.,2020).Excessive vascular inflammation is clinically known as vasculitis,diagnosed by blood test,imaging and biopsy.Vasculitis not only thickens the blood vessel wall,causing blood flow reduction and insufficient delivery of oxygen and nutrients,but also triggers inflammatory responses in secondary sites,or even the whole body.展开更多
The generation of induced tissue-specific stem cells has been hampered by the lack of well-established methods for the maintenance of pure tissue-specific stem cells like the ones we have for embryonic stem （ES） cel...The generation of induced tissue-specific stem cells has been hampered by the lack of well-established methods for the maintenance of pure tissue-specific stem cells like the ones we have for embryonic stem （ES） cell cultures. Using a cocktail of cytokines and small molecules, we dem- onstrate that primitive neural stem （NS） cells derived from mouse ES cells and rat embryos can be maintained. Furthermore, using the same set of cytokines and small molecules, we show that induced NS （iNS） cells can be generated from rat fibroblasts by forced expression of the transcrip- tional factors Oct4, Sox2 and c-Myc. The generation and long-term maintenance of iNS cells could have wide and momentous implications.展开更多
基金supported by the National Natural Science Foundation of China(Grant Nos.:82071287,81870916)the National Natural Science Foundation of China(Grant No.:81971097)+3 种基金the Basic Public Interests Research Plan of Zhejiang Province,China(Grant No.:GF18H090006)the National Natural Science Foundation of China(Grant No.:81701214)the National Natural Science Foundation of China(Grant No.:82001299)the Natural Science Foundation of Zhejiang Province,China(Grant No.:TGD23C040017).
文摘The role of glial scar after intracerebral hemorrhage(ICH)remains unclear.This study aimed to investigate whether microglia-astrocyte interaction affects glial scar formation and explore the specific function of glial scar.We used a pharmacologic approach to induce microglial depletion during different ICH stages and examine how ablating microglia affects astrocytic scar formation.Spatial transcriptomics(ST)analysis was performed to explore the potential ligand-receptor pair in the modulation of microglia-astrocyte interaction and to verify the functional changes of astrocytic scars at different periods.During the early stage,sustained microglial depletion induced disorganized astrocytic scar,enhanced neutrophil infiltration,and impaired tissue repair.ST analysis indicated that microglia-derived insulin like growth factor 1(IGF1)modulated astrocytic scar formation via mechanistic target of rapamycin(mTOR)signaling activation.Moreover,repopulating microglia(RM)more strongly activated mTOR signaling,facilitating a more protective scar formation.The combination of IGF1 and osteopontin(OPN)was necessary and sufficient for RM function,rather than IGF1 or OPN alone.At the chronic stage of ICH,the overall net effect of astrocytic scar changed from protective to destructive and delayed microglial depletion could partly reverse this.The vital insight gleaned from our data is that sustained microglial depletion may not be a reasonable treatment strategy for early-stage ICH.Inversely,early-stage IGF1/OPN treatment combined with late-stage PLX3397 treatment is a promising therapeutic strategy.This prompts us to consider the complex temporal dynamics and overall net effect of microglia and astrocytes,and develop elaborate treatment strategies at precise time points after ICH.
基金supported by the National Institutes of Health(NIH),Nos.R01AG061288,R03AG063287,R01NS110687,R21AG066090,and 1RF1NS122060Bright Focus Foundation,No.A2019218SU.S.Department of Defense grant No.W81XWH2010424(to ZZ).
文摘Vasculature is the interface between tissue and circulation.It consists of endothelial cells,mural cells including vascular smooth muscle cells and pericytes,and other perivascular cells including macrophages and fibroblasts(Sweeney et al.,2019).The vascular system not only delivers oxygen and nutrients,but also shuttles the immune cells around.As the first line of defense,the vascular system also senses the changes in surrounding tissue,particularly inflammation.Vascular inflammation can occur in blood vessels of all sizes in any organ.It has a complex etiology,including infections such as coronavirus disease-19(COVID-19),and chronic condi t ions such as diabetes,hypertension and neurodegenerative diseases(Hanafi et al.,2020).Excessive vascular inflammation is clinically known as vasculitis,diagnosed by blood test,imaging and biopsy.Vasculitis not only thickens the blood vessel wall,causing blood flow reduction and insufficient delivery of oxygen and nutrients,but also triggers inflammatory responses in secondary sites,or even the whole body.
基金supported by USC startup fund to QLY and in part by NIH(Grant No.R01OD010926) to QLY
文摘The generation of induced tissue-specific stem cells has been hampered by the lack of well-established methods for the maintenance of pure tissue-specific stem cells like the ones we have for embryonic stem （ES） cell cultures. Using a cocktail of cytokines and small molecules, we dem- onstrate that primitive neural stem （NS） cells derived from mouse ES cells and rat embryos can be maintained. Furthermore, using the same set of cytokines and small molecules, we show that induced NS （iNS） cells can be generated from rat fibroblasts by forced expression of the transcrip- tional factors Oct4, Sox2 and c-Myc. The generation and long-term maintenance of iNS cells could have wide and momentous implications.
