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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 ?-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.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.

SUBMITTER: Suh YG

PROVIDER: S-EPMC3427419 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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

Suh Yang-Gun YG Kim Ja Kyung JK Byun Jin-Seok JS Yi Hyon-Seung HS Lee Young-Sun YS Eun Hyuk Soo HS Kim So Yeon SY Han Kwang-Hyub KH Lee Kwan Sik KS Duester Gregg G Friedman Scott L SL Jeong Won-Il WI

Hepatology (Baltimore, Md.) 20121009 5

<h4>Unlabelled</h4>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 investig ...[more]

PMID: 22544759

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Project description:BACKGROUND:Activated fibroblasts (myofibroblasts) play a critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear, warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast progenitor cells (BM-FPCs) in pressure overload-induced cardiac fibrosis. We have previously shown that interleukin-10 (IL10) suppresses pressure overload-induced cardiac fibrosis; however, the role of IL10 in inhibition of BM-FPC-mediated cardiac fibrosis is not known. We hypothesized that IL10 inhibits pressure overload-induced homing of BM-FPCs to the heart and their transdifferentiation to myofibroblasts and thus attenuates cardiac fibrosis. METHODS:Pressure overload was induced in wild-type (WT) and IL10 knockout (IL10KO) mice by transverse aortic constriction. To determine the bone marrow origin, chimeric mice were created with enhanced green fluorescent protein WT mice marrow to the IL10KO mice. For mechanistic studies, FPCs were isolated from mouse bone marrow. RESULTS:Pressure overload enhanced BM-FPC mobilization and homing in IL10KO mice compared with WT mice. Furthermore, WT bone marrow (from enhanced green fluorescent protein mice) transplantation in bone marrow-depleted IL10KO mice (IL10KO chimeric mice) reduced transverse aortic constriction-induced BM-FPC mobilization compared with IL10KO mice. Green fluorescent protein costaining with ?-smooth muscle actin or collagen 1? in left ventricular tissue sections of IL10KO chimeric mice suggests that myofibroblasts were derived from bone marrow after transverse aortic constriction. Finally, WT bone marrow transplantation in IL10KO mice inhibited transverse aortic constriction-induced cardiac fibrosis and improved heart function. At the molecular level, IL10 treatment significantly inhibited transforming growth factor-?-induced transdifferentiation and fibrotic signaling in WT BM-FPCs in vitro. Furthermore, fibrosis-associated microRNA (miRNA) expression was highly upregulated in IL10KO-FPCs compared with WT-FPCs. Polymerase chain reaction-based selective miRNA analysis revealed that transforming growth factor-?-induced enhanced expression of fibrosis-associated miRNAs (miRNA-21, -145, and -208) was significantly inhibited by IL10. Restoration of miRNA-21 levels suppressed the IL10 effects on transforming growth factor-?-induced fibrotic signaling in BM-FPCs. CONCLUSIONS:Our findings suggest that IL10 inhibits BM-FPC homing and transdifferentiation to myofibroblasts in pressure-overloaded myocardium. Mechanistically, we show for the first time that IL10 suppresses Smad-miRNA-21-mediated activation of BM-FPCs and thus modulates cardiac fibrosis.

Project description:Endothelial progenitor cell (EPC)-based therapy has immense potential to promote cardiac neovascularization and attenuate ischemic injury. Functional benefits of EPCs and other adult stem cell therapies largely involve paracrine mechanisms and exosomes secreted by stem cells are emerging as pivotal paracrine entity of stem/progenitor cells. However, modest outcomes after EPC-/stem cell-based clinical trials suggest that stem cell/exosome function might be modulated by stimuli they encounter in ischemic tissues, including systemic inflammation. We hypothesized that EPCs under inflammatory stress might produce exosomes of altered and dysfunctional content, which may compromise EPC repair in ischemic heart disease. We have previously shown that EPCs obtained from interleukin-10 knockout (IL-10KO) mice (model mimicking systemic inflammation) display impaired angiogenic functions. Whether IL-10KO-EPC-derived exosomes inherit their parental dysfunctional phenotype and whether inflammatory environment alters the cargo of their secreted exosomes are not known. After cell expansion from IL-10KO and wild-type (WT) mice, we isolated exosomes and compared their functions in terms of effect on cell survival, proliferation, migration, and angiogenic capacity in vitro. WT-EPC-Exo treatment enhanced endothelial cell proliferation and tube formation, and inhibited apoptosis, whereas IL-10KO-Exo exhibited impaired or even detrimental effects, suggesting that the reparative capacity of WT-EPC-Exo is lost in exosomes derived from IL-10-KO-EPCs. Deep RNA sequencing and proteomic analyses to compare WT and IL-10KO-Exo revealed drastically altered exosome cargo. Importantly, IL-10KO-EPC-Exo were highly enriched in microRNAs and proteins that promote inflammation and apoptosis and inhibit angiogenesis. Through modulation of a specific enriched miRNA (miR-375), we partially rescued IL-10KO-EPC-Exo dysfunction. Thus, our study revealed that EPC exosomes display impaired function under inflammatory stimulus through changed exosome contents, and the dysfunction can be rescued by modulation of a specific target packed in exosomes.

Project description:AimRecent reports have shown the capacity of mesenchymal stem cells (MSCs) to differentiate into hepatocytes in vitro and in vivo. MSCs administration could repair injured liver, lung, or heart through reducing inflammation, collagen deposition, and remodeling. These results provide a clue to treatment of liver fibrosis. The aim of this study was to investigate the effect of infusion of bone marrow (BM)-derived MSCs on the experimental liver fibrosis in rats.MethodsMSCs isolated from BM in male Fischer 344 rats were infused to female Wistar rats induced with carbon tetrachloride (CCl4) or dimethylnitrosamine (DMN). There were two random groups on the 42nd d of CCl4:CCl4/MSCs, to infuse a dose of MSCs alone; CCl4/saline, to infuse the same volume of saline as control. There were another three random groups after exposure to DMN: DMN10/MSCs, to infuse the same dose of MSCs on d 10; DMN10/saline, to infuse the same volume of saline on d 10; DMN20/MSCs, to infuse the same dose of MSCs on d 20. The morphological and behavioral changes of rats were monitored everyday. After 4-6 wk of MSCs administration, all rats were killed and fibrosis index were assessed by histopathology and radioimmunoassay. Smooth muscle alpha-actin (alpha-SMA) of liver were tested by immunohistochemistry and quantified by IBAS 2.5 software. Male rats sex determination region on the Y chromosome (sry) gene were explored by PCR.ResultsCompared to controls, infusion of MSCs reduced the mortality rates of incidence in CCl4-induced model (10% vs 20%) and in DMN-induced model (20-40% vs 90%). The amount of collagen deposition and alpha-SMA staining was about 40-50% lower in liver of rats with MSCs than that of rats without MSCs. The similar results were observed in fibrosis index. And the effect of the inhibition of fibrogenesis was greater in DMN10/MSCs than in DMN20/MSCs. The sry gene was positive in the liver of rats with MSCs treatment by PCR.ConclusionMSCs treatment can protect against experimental liver fibrosis in CCl4-induced or DMN-induced rats and the mechanisms of the anti-fibrosis by MSCs will be studied further.

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

Publications

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

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