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CD11b+ Gr1+ bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice

 Yang-Gun Suh  ;  Ja Kyung Kim  ;  Jin-Seok Byun  ;  Hyon-Seung Yi  ;  Young-Sun Lee  ;  Hyuk Soo Eun  ;  So Yeon Kim  ;  Kwang-Hyub Han  ;  Kwan Sik Lee  ;  Gregg Duester  ;  Scott L. Friedman  ;  Won-Il Jeong 
 HEPATOLOGY, Vol.56(5) : 1902-1912, 2012 
Journal Title
Issue Date
Actins/metabolism ; Animals ; Bone Marrow Cells/immunology ; Bone Marrow Cells/metabolism* ; Bone Marrow Transplantation ; CD11b Antigen/metabolism ; CD4 Antigens/metabolism ; Carbon Tetrachloride ; Cell Communication ; Chemokine CCL2/genetics ; Chemokine CCL2/metabolism ; Collagen Type I/metabolism ; Forkhead Transcription Factors/metabolism ; Hepatic Stellate Cells/immunology ; Hepatic Stellate Cells/metabolism* ; Humans ; Interleukin-1/genetics ; Interleukin-1/metabolism ; Interleukin-10/immunology ; Interleukin-10/metabolism* ; Interleukin-2 Receptor alpha Subunit/metabolism ; Liver Cirrhosis/chemically induced ; Liver Cirrhosis/immunology* ; Liver Cirrhosis/metabolism* ; Liver Cirrhosis/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Mice, Transgenic ; RNA, Messenger/metabolism ; Receptors, Chemokine/metabolism ; Statistics, Nonparametric ; T-Lymphocytes, Regulatory/immunology* ; T-Lymphocytes, Regulatory/metabolism ; Transforming Growth Factor beta1/genetics ; Transforming Growth Factor beta1/metabolism
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. Conclusion : 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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiation Oncology (방사선종양학교실) > 1. Journal Papers
Yonsei Authors
Kim, Ja Kyung(김자경) ORCID logo https://orcid.org/0000-0001-5025-6846
Suh, Yang Gun(서양권)
Lee, Kwan Sik(이관식) ORCID logo https://orcid.org/0000-0002-3672-1198
Han, Kwang-Hyub(한광협) ORCID logo https://orcid.org/0000-0003-3960-6539
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