Inflammation plays a crucial role in the regeneration of fish and avian retinas.However,how inflammation regulates Müller glia(MG)reprogramming remains unclear.Here,we used single-cell RNA sequencing to investiga...Inflammation plays a crucial role in the regeneration of fish and avian retinas.However,how inflammation regulates Müller glia(MG)reprogramming remains unclear.Here,we used single-cell RNA sequencing to investigate the cell heterogeneity and interactions of MG and immune cells in the regenerating zebrafish retina.We first showed that two types of quiescent MG(resting MG1 and MG2)reside in the uninjured retina.Following retinal injury,resting MG1 transitioned into an activated state expressing known reprogramming genes,while resting MG2 gave rise to rod progenitors.We further showed that retinal microglia can be categorized into three subtypes(microglia-1,microglia-2,and proliferative)and pseudotime analysis demonstrated dynamic changes in microglial status following retinal injury.Analysis of cell–cell interactions indicated extensive crosstalk between immune cells and MG,with many interactions shared among different immune cell types.Finally,we showed that inflammation activated Jak1–Stat3 signaling in MG,promoting their transition from a resting to an activated state.Our study reveals the cell heterogeneity and crosstalk of immune cells and MG in zebrafish retinal repair,and may provide valuable insights into future mammalian retina regeneration.展开更多
The transcription factor Sox11 plays important roles in retinal neurogenesis during vertebrate eye development.However,its function in retina regeneration remains elusive.Here we report that Sox11 b,a zebrafish Sox11 ...The transcription factor Sox11 plays important roles in retinal neurogenesis during vertebrate eye development.However,its function in retina regeneration remains elusive.Here we report that Sox11 b,a zebrafish Sox11 homolog,regulates the migration and fate determination of Müller glia-derived progenitors(MGPCs)in an adult zebrafish model of mechanical retinal injury.Following a stab injury,the expression of Sox11 b was induced in proliferating MGPCs in the retina.Sox11 b knockdown did not affect MGPC formation at 4 days post-injury,although the nuclear morphology and subsequent radial migration of MGPCs were alte red.At 7 days post-injury,Sox11 b knockdown res ulted in an increased proportion of MGPCs in the inner retina and a decreased propo rtion of MGPCs in the outer nuclear layer,compared with controls.Furthermore,Sox11 b knockdown led to reduced photoreceptor regeneration,while it increased the numbe rs of newborn amacrines and retinal ganglion cells.Finally,quantitative polymerase chain reaction analysis revealed that Sox11 b regulated the expression of Notch signaling components in the retina,and Notch inhibition partially recapitulated the Sox11 b knockdown phenotype,indicating that Notch signaling functions downstream of Sox11 b.Our findings imply that Sox11 b plays key roles in MGPC migration and fate determination during retina regeneration in zebrafish,which may have critical im plications for future explorations of retinal repair in mammals.展开更多
基金supported by the National Natural Science Foundation of China,Nos.81970820(to HX),31771644(to JL),31930068(to JL),82371176(to JL),81801331(to LC)National Key Research and Development Project of China.Nos.2017YFA0104100(to JL),2017YFA0701304(to HX)+1 种基金Shanghai Yangzhi Rehabilitation Hospital(Shanghai Sunshine Rehabilitation Center)Talent Introduction Plan,No.KYPT202204(to LC)the Fundamental Research Funds for the Central Universities,No.22120230292(to JL)。
文摘Inflammation plays a crucial role in the regeneration of fish and avian retinas.However,how inflammation regulates Müller glia(MG)reprogramming remains unclear.Here,we used single-cell RNA sequencing to investigate the cell heterogeneity and interactions of MG and immune cells in the regenerating zebrafish retina.We first showed that two types of quiescent MG(resting MG1 and MG2)reside in the uninjured retina.Following retinal injury,resting MG1 transitioned into an activated state expressing known reprogramming genes,while resting MG2 gave rise to rod progenitors.We further showed that retinal microglia can be categorized into three subtypes(microglia-1,microglia-2,and proliferative)and pseudotime analysis demonstrated dynamic changes in microglial status following retinal injury.Analysis of cell–cell interactions indicated extensive crosstalk between immune cells and MG,with many interactions shared among different immune cell types.Finally,we showed that inflammation activated Jak1–Stat3 signaling in MG,promoting their transition from a resting to an activated state.Our study reveals the cell heterogeneity and crosstalk of immune cells and MG in zebrafish retinal repair,and may provide valuable insights into future mammalian retina regeneration.
基金supported by the National Key Research and Development Project of China,Nos.2017YFA0104100(to JL),2017YFA0701304(to HX)National Natural Science Foundation of China Nos.81970820(to HX),31930068(to JL)。
文摘The transcription factor Sox11 plays important roles in retinal neurogenesis during vertebrate eye development.However,its function in retina regeneration remains elusive.Here we report that Sox11 b,a zebrafish Sox11 homolog,regulates the migration and fate determination of Müller glia-derived progenitors(MGPCs)in an adult zebrafish model of mechanical retinal injury.Following a stab injury,the expression of Sox11 b was induced in proliferating MGPCs in the retina.Sox11 b knockdown did not affect MGPC formation at 4 days post-injury,although the nuclear morphology and subsequent radial migration of MGPCs were alte red.At 7 days post-injury,Sox11 b knockdown res ulted in an increased proportion of MGPCs in the inner retina and a decreased propo rtion of MGPCs in the outer nuclear layer,compared with controls.Furthermore,Sox11 b knockdown led to reduced photoreceptor regeneration,while it increased the numbe rs of newborn amacrines and retinal ganglion cells.Finally,quantitative polymerase chain reaction analysis revealed that Sox11 b regulated the expression of Notch signaling components in the retina,and Notch inhibition partially recapitulated the Sox11 b knockdown phenotype,indicating that Notch signaling functions downstream of Sox11 b.Our findings imply that Sox11 b plays key roles in MGPC migration and fate determination during retina regeneration in zebrafish,which may have critical im plications for future explorations of retinal repair in mammals.
