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 (BMC) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMC. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMC showing antifibrotic effects in mice with carbon tetrachloride-induced liver fibrosis. An interaction between BMC and activated hepatic stellate cells (HSCs) was investigated using in vitro co-culturing system. Within 24 hours, infused BMC were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10-deficient (IL-10−/−) BMC failed to reproduce these effects in the fibrotic livers. Intriguingly, in isolated cells, CD11b+Gr1highF4/80− and CD11b+Gr1+F4/80+ BMC expressed more IL-10 after co-culturing 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 BMC were co-cultured with IL-6−/− and retinaldehyde dehydrogenase 1−/− HSCs. Similar to murine data, human BMC expressed more IL-10 after co-culturing 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 BMC (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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“…39 In addition, MSCs might attenuate hepatic fibrosis through suppression of hepatic stellate cells by the secretion of interleukins 6 and 10. 34,35 In our study, both the hepatocyte-treated and hepatocyte-differentiated MSC-treated groups succeeded in the amelioration of CCl4-induced fibrosis. In agreement with this observation, Badrawy and associates 40 and Nagata and associates, 7 using injected rat hepatocytes, found improved liver fibrosis by formation of hepatocyte sheets in a mouse CCl4 liverinjured model.…”

“…Our results are in agreement with studies that focused on investigating antifibrotic effects on the injured liver in animal models of liver fibrosis. [33][34][35][36] Several mechanisms have been suggested for MSC-mediated improvements in liver function and cirrhosis severity. Mesenchymal stem cells have been shown to be able to produce matrix metalloproteinase, an enzyme capable of degrading the extracellular matrix, which alleviates hepatic cirrhosis directly.…”

“…In agreement with this observation, Badrawy and associates 40 and Nagata and associates, 7 using injected rat hepatocytes, found improved liver fibrosis by formation of hepatocyte sheets in a mouse CCl4 liverinjured model. In addition, Piryaei and associates 34 reported reductions in pathologic insult of the liver in chronic liver disease using in vitro hepatocytedifferentiated MSCs.…”

Cytokine Production and Signaling in Stellate Cells

“…IL-10 inhibits procollagen α(1) expression at the transcriptional level, and may have important anti-fibrogenic properties [139,143], as also indicated by the anti-fibrogenic actions of transgenic IL-10 expression in hepatocytes [144]. Bone marrow-derived cells may be an additional source of IL-10, resulting in a limitation of fibrosis [145]. HSCs are an additional source of IL-10, and release of this cytokine ameliorates experimental alcoholic liver disease following activation of toll-like receptor-3 [141].…”

Treating end-stage liver diseases with mesenchymal stem cells: An oak is not felled at one stroke

“…HGF may also play a bene icial role in suppressing production of transforming growth factor (TGF)-β, the main player in the pathway activating the HSCs 16,17 . IL-6 and IL-10 may attenuate hepatic ibrosis through suppression of HSCs [18][19][20] . (c) MSCs may dissolve ibrosis directly.…”