title: Single and local blockade of interleukin-6 signaling promotes neuronal differentiation from transplanted embryonic stem cell-derived neural precursor cells.
abstract: Safe and efficient transplantation of embryonic stem (ES) cells to the brain requires that local inflammatory and immune responses to allogeneic grafts are inhibited. To investigate cytokines that affect graft cell survival and differentiation, we used stromal cell-derived inducing activity to induce the differentiation of neural progenitor cells (NPCs) from mouse ES cells and transplanted the NPCs into mouse brain. Examination of surrounding brain tissue revealed elevated expression levels of interleukin (IL)-1β, IL-4, and IL-6 in response to NPC transplantation. Among these, only IL-6 reduced neuronal differentiation and promoted glial differentiation in vitro. When we added anti-IL-6 receptor antibodies to NPCs during transplantation, this single and local blockade of IL-6 signaling reduced the accumulation of host-derived leukocytes, including microglia. Furthermore, it also promoted neuronal differentiation and reduced glial differentiation from the grafted NPCs to an extent similar to that with systemic and continuous administration of cyclosporine A. These results suggest that local administration of anti-IL-6 receptor antibodies with NPCs may promote neuronal differentiation during the treatment of neurological diseases with cell replacement therapy.
authors.affiliation: Department of Biological Repair, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Gomi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Aoki
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takagi
authors.forename: Masaki
authors.initials: M
authors.lastname: Nishimura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ohsugi
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mihara
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nozaki
authors.forename: Nobuo
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Susumu
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Jun
authors.initials: J
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001921:Brain / Q000166:cytology* / Q000276:immunology / Q000601:surgery; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000502:physiology; D006085:Graft Survival / Q000276:immunology / Q000502:physiology*; D015850:Interleukin-6 / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000502:physiology / Q000637:transplantation; D033581:Stem Cell Transplantation; D000093242:Interleukin-6 Inhibitors
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors