Continuous immunosuppression has been widely used in xenografts into non-human primate brains.However,how immune responses change after transplantation in host brains under continuous immunosuppressive adminis-tration...Continuous immunosuppression has been widely used in xenografts into non-human primate brains.However,how immune responses change after transplantation in host brains under continuous immunosuppressive adminis-tration and whether immunosuppression can be withdrawn to mitigate side effects remain unclear.Human induced neural stem/progenitor cells(iNPCs)have shown long-term survival and efficient neuronal differentiation in primate brains.Here,we evaluate the immune responses in primate brains triggered by human grafts.The results show that the immune responses,including the evident activation of microglia and the strong infiltration of lymphocytes(both T-and B-cells),are caused by xenografts at 4 months post transplantation(p.t.),but significantly reduced at 8 months p.t.under continuous administration of immunosuppressant Cyclosporin A.However,early immuno-suppressant withdrawal at 5 months p.t.results in severe immune responses at 10 months p.t.These results suggest that continuous long-term immunosuppression is required for suppressing immune responses to xenografts in pri-mate brains.展开更多
Background:Cell replacement therapy has been envisioned as a promising treatment for neurodegenerative diseases.Due to the ethical concerns of ESCs-derived neural progenitor cells(NPCs)and tumorigenic potential of iPS...Background:Cell replacement therapy has been envisioned as a promising treatment for neurodegenerative diseases.Due to the ethical concerns of ESCs-derived neural progenitor cells(NPCs)and tumorigenic potential of iPSCs,reprogramming of somatic cells directly into multipotent NPCs has emerged as a preferred approach for cell transplantation.Methods:Mouse astrocytes were reprogrammed into NPCs by the overexpression of transcription factors(TFs)Foxg1,Sox2,and Brn2.The generation of subtypes of neurons was directed by the force expression of cell-type specific TFs Lhx8 or Foxa2/Lmx1a.Results:Astrocyte-derived induced NPCs(AiNPCs)share high similarities,including the expression of NPC-specific genes,DNA methylation patterns,the ability to proliferate and differentiate,with the wild type NPCs.The AiNPCs are committed to the forebrain identity and predominantly differentiated into glutamatergic and GABAergic neuronal subtypes.Interestingly,additional overexpression of TFs Lhx8 and Foxa2/Lmx1a in AiNPCs promoted cholinergic and dopaminergic neuronal differentiation,respectively.Conclusions:Our studies suggest that astrocytes can be converted into AiNPCs and lineage-committed AiNPCs can acquire differentiation potential of other lineages through forced expression of specific TFs.Understanding the impact of the TF sets on the reprogramming and differentiation into specific lineages of neurons will provide valuable strategies for astrocyte-based cell therapy in neurodegenerative diseases.展开更多
基金National Key Basic Research and Development Program of China(2019YFA0801402,2018YFA0107200,2018YFA0801402,2018YFA0800100)Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16020501,XDA16020404)National Natural Science Foundation of China(32130030,31900454).
文摘Continuous immunosuppression has been widely used in xenografts into non-human primate brains.However,how immune responses change after transplantation in host brains under continuous immunosuppressive adminis-tration and whether immunosuppression can be withdrawn to mitigate side effects remain unclear.Human induced neural stem/progenitor cells(iNPCs)have shown long-term survival and efficient neuronal differentiation in primate brains.Here,we evaluate the immune responses in primate brains triggered by human grafts.The results show that the immune responses,including the evident activation of microglia and the strong infiltration of lymphocytes(both T-and B-cells),are caused by xenografts at 4 months post transplantation(p.t.),but significantly reduced at 8 months p.t.under continuous administration of immunosuppressant Cyclosporin A.However,early immuno-suppressant withdrawal at 5 months p.t.results in severe immune responses at 10 months p.t.These results suggest that continuous long-term immunosuppression is required for suppressing immune responses to xenografts in pri-mate brains.
基金This work was supported in part by research grants from the National Basic Research Program of China(973 ProgramGrant No.2014CB965001 to JZ)Innovative Research Groups of the National Natural Science Foundation of China(#81221001 to JZ)+2 种基金Joint Research Fund for Overseas Chinese,Hong Kong and Macao Young Scientists of the National Natural Science Foundation of China(#81329002 to JZ)the National Institutes of Health:2R56NS041858-15A1(JZ),1R01NS097195-01(JZ),and R03 NS094071-01(YH)the State of Nebraska,DHHS-LB606 Stem Cell 2009-10 to JZ.
文摘Background:Cell replacement therapy has been envisioned as a promising treatment for neurodegenerative diseases.Due to the ethical concerns of ESCs-derived neural progenitor cells(NPCs)and tumorigenic potential of iPSCs,reprogramming of somatic cells directly into multipotent NPCs has emerged as a preferred approach for cell transplantation.Methods:Mouse astrocytes were reprogrammed into NPCs by the overexpression of transcription factors(TFs)Foxg1,Sox2,and Brn2.The generation of subtypes of neurons was directed by the force expression of cell-type specific TFs Lhx8 or Foxa2/Lmx1a.Results:Astrocyte-derived induced NPCs(AiNPCs)share high similarities,including the expression of NPC-specific genes,DNA methylation patterns,the ability to proliferate and differentiate,with the wild type NPCs.The AiNPCs are committed to the forebrain identity and predominantly differentiated into glutamatergic and GABAergic neuronal subtypes.Interestingly,additional overexpression of TFs Lhx8 and Foxa2/Lmx1a in AiNPCs promoted cholinergic and dopaminergic neuronal differentiation,respectively.Conclusions:Our studies suggest that astrocytes can be converted into AiNPCs and lineage-committed AiNPCs can acquire differentiation potential of other lineages through forced expression of specific TFs.Understanding the impact of the TF sets on the reprogramming and differentiation into specific lineages of neurons will provide valuable strategies for astrocyte-based cell therapy in neurodegenerative diseases.
