Intestinal stem cells(ISCs)promote tissue repair after genotoxic or immune-mediated injury.However,ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses,such as inte...Intestinal stem cells(ISCs)promote tissue repair after genotoxic or immune-mediated injury.However,ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses,such as interferonγ(IFNγ)-mediated killing.In mouse models of radiation therapy-induced gut damage and in biopsies from patients who underwent allogeneic hematopoietic stem cell transplantation,we observed IFNγexpression by intestinal Treg cells.Treg cells leverage combined IFNγand interleukin 10(IL-10)stimulation of ISCs to nurture the growth of intestinal organoids through the activation of the mTORC1 and Myc pathways.Similarly,Treg cells or the combined addition of recombinant IFNγand IL-10 promoted the regeneration of organoids after irradiation,and both cytokines were essential for ensuring epithelial regeneration following acute intestinal tissue injury in vivo.The exposure of organoids to growth factor-free culture conditions revealed distinct EGF-like properties of IFNγand Wnt-like properties of IL-10.While IFNγrapidly induced epithelial proliferation,it depleted the pool of ISCs in vitro.Only the combination of IFNγand IL10 led to epithelial proliferation and organoid growth while simultaneously ensuring ISC maintenance over time.Our results reveal a context-dependent role of inflammatory signaling in ISCs,through which Treg cells promote epithelial repair following therapyinduced injury.展开更多
基金funded by the Else Kröner Fresenius-Stiftung(2019_A149 and 2022_EKMS.26 to J.C.F.)the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)-Projektnummer 360372040-SFB 1335(to F.B.,H.P.,S.H.,and K.S.)+12 种基金Projektnummer 395357507-SFB 1371(P04 to D.H.B.and E.H.,P05 to H.P.,P11 to M.T.and J.C.F.,Z02 to K.S.,seed funding to E.T.O.)Projektnummer 324392634-TRR 221(to H.P.,E.H.,M.B-H.,M.R.,M.F.,P.H.,M.E.,D.W.,and W.H.)Projektnummer BA 2851/6-1(to F.B.)Projektnummer PO 1575/5-1(to H.P.)Projektnummer 509149993-TRR 374(to E.V.,M.B-H.)Bavarian Cancer Research Centre(BZFK,to H.P.,W.H.,and F.B.)the German Cancer Aid(70114547 to H.P.,70113964 to J.C.F.)the Wilhelm Sander Foundation(2023.072.1 to J.C.F.,2021.041.1 to S.H.,2021.040.1 to H.P.)the European Hematology Association(to H.P.)a Mechtild Harf Research Grant from the DKMS Foundation for Giving Life(to H.P.)a Young Investigator Award by the Melanoma Research Alliance(to S.H.)the German JoséCarreras leukemia foundation(DJCLS 07 R/2020 to S.H.)funded/co-funded by the European Union(project MICROBOTS,Grant No.101124680 to H.P.).
文摘Intestinal stem cells(ISCs)promote tissue repair after genotoxic or immune-mediated injury.However,ISCs are particularly sensitive to various stressors and primary targets of overwhelming immune responses,such as interferonγ(IFNγ)-mediated killing.In mouse models of radiation therapy-induced gut damage and in biopsies from patients who underwent allogeneic hematopoietic stem cell transplantation,we observed IFNγexpression by intestinal Treg cells.Treg cells leverage combined IFNγand interleukin 10(IL-10)stimulation of ISCs to nurture the growth of intestinal organoids through the activation of the mTORC1 and Myc pathways.Similarly,Treg cells or the combined addition of recombinant IFNγand IL-10 promoted the regeneration of organoids after irradiation,and both cytokines were essential for ensuring epithelial regeneration following acute intestinal tissue injury in vivo.The exposure of organoids to growth factor-free culture conditions revealed distinct EGF-like properties of IFNγand Wnt-like properties of IL-10.While IFNγrapidly induced epithelial proliferation,it depleted the pool of ISCs in vitro.Only the combination of IFNγand IL10 led to epithelial proliferation and organoid growth while simultaneously ensuring ISC maintenance over time.Our results reveal a context-dependent role of inflammatory signaling in ISCs,through which Treg cells promote epithelial repair following therapyinduced injury.
