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

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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+Gr1highF4/80- 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+Gr1highF4/80- and CD11b+Gr1+F4/80+ cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis.

Original languageEnglish
Pages (from-to)1902-1912
Number of pages11
JournalHepatology
Volume56
Issue number5
DOIs
Publication statusPublished - 2012 Nov 1
Externally publishedYes

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Bone Marrow Cells
Liver Cirrhosis
Interleukin-10
Hepatic Stellate Cells
Liver
Retinaldehyde
Carbon Tetrachloride
Regulatory T-Lymphocytes
Cell- and Tissue-Based Therapy
Smooth Muscle
Actins
Interleukin-6
Oxidoreductases
Collagen
Animal Models
Macrophages
Clinical Trials

ASJC Scopus subject areas

  • Hepatology

Cite this

Suh, Y. G., Kim, J. K., Byun, J. S., Yi, H. S., Lee, Y-S., Eun, H. S., ... Jeong, W. I. (2012). CD11b+ Gr1+ bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice. Hepatology, 56(5), 1902-1912. https://doi.org/10.1002/hep.25817

CD11b+ Gr1+ bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice. / Suh, Yang Gun; Kim, Ja Kyung; Byun, Jin Seok; Yi, Hyon Seung; Lee, Young-Sun; Eun, Hyuk Soo; Kim, So Yeon; Han, Kwang Hyub; Lee, Kwan Sik; Duester, Gregg; Friedman, Scott L.; Jeong, Won Il.

In: Hepatology, Vol. 56, No. 5, 01.11.2012, p. 1902-1912.

Research output: Contribution to journalArticle

Suh, YG, Kim, JK, Byun, JS, Yi, HS, Lee, Y-S, Eun, HS, Kim, SY, Han, KH, Lee, KS, Duester, G, Friedman, SL & Jeong, WI 2012, 'CD11b+ Gr1+ bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice', Hepatology, vol. 56, no. 5, pp. 1902-1912. https://doi.org/10.1002/hep.25817
Suh, Yang Gun ; Kim, Ja Kyung ; Byun, Jin Seok ; Yi, Hyon Seung ; Lee, Young-Sun ; Eun, Hyuk Soo ; Kim, So Yeon ; Han, Kwang Hyub ; Lee, Kwan Sik ; Duester, Gregg ; Friedman, Scott L. ; Jeong, Won Il. / CD11b+ Gr1+ bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice. In: Hepatology. 2012 ; Vol. 56, No. 5. pp. 1902-1912.
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AU - Lee, Young-Sun

AU - Eun, Hyuk Soo

AU - Kim, So Yeon

AU - Han, Kwang Hyub

AU - Lee, Kwan Sik

AU - Duester, Gregg

AU - Friedman, Scott L.

AU - Jeong, Won Il

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AB - 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+Gr1highF4/80- 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+Gr1highF4/80- 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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