title: CD11b(+)  Gr1(+)  bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice.
abstract: Clinical trials and animal models suggest that infusion of bone marrow cells (BMCs) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMCs. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMCs showing antifibrotic effects in mice with carbon tetrachloride-induced liver fibrosis. An interaction between BMCs and activated hepatic stellate cells (HSCs) was investigated using an in vitro coculturing system. Within 24 hours, infused BMCs were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, and expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10-deficient (IL-10(-/-) ) BMCs failed to reproduce these effects in fibrotic livers. Intriguingly, in isolated cells, CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) BMCs expressed more IL-10 after coculturing with activated HSCs, leading to suppressed expression of collagen and α-smooth muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMCs were cocultured with IL-6(-/-) and retinaldehyde dehydrogenase 1(-/-) HSCs. Similar to murine data, human BMCs expressed more IL-10 after coculturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion.
  
  
  CONCLUSIONS
  Activated HSCs increase IL-10 expression in BMCs (CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis.
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: Yang-Gun
authors.initials: YG
authors.lastname: Suh
authors.forename: Ja Kyung
authors.initials: JK
authors.lastname: Kim
authors.forename: Jin-Seok
authors.initials: JS
authors.lastname: Byun
authors.forename: Hyon-Seung
authors.initials: HS
authors.lastname: Yi
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Lee
authors.forename: Hyuk Soo
authors.initials: HS
authors.lastname: Eun
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Kwang-Hyub
authors.initials: KH
authors.lastname: Han
authors.forename: Kwan Sik
authors.initials: KS
authors.lastname: Lee
authors.forename: Gregg
authors.initials: G
authors.lastname: Duester
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.forename: Won-Il
authors.initials: WI
authors.lastname: Jeong
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D039481:CD11b Antigen / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D002251:Carbon Tetrachloride; D002450:Cell Communication; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D039481:CD11b Antigen; D015704:CD4 Antigens; D018932:Chemokine CCL2; D024042:Collagen Type I; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C503133:Gr-1 protein, mouse; D007375:Interleukin-1; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; D016753:Interleukin-10; D002251:Carbon Tetrachloride