Hepatic Stellate Cells Regulate Immune Response by Way of Induction of Myeloid Suppressor Cells in Mice Δσ

Abstract

Although organ transplants have been applied for decades, outcomes of somatic cell transplants remain disappointing, presumably due to lack of appropriate supporting stromal cells. Thus, cotransplantation with liver stromal cells, hepatic stellate cells (HSC), achieves long-term survival of islet allografts in mice by way of induction of effector T cell apoptosis and generation of regulatory T (Treg) cells. In this study we provide evidence both in vitro and in vivo that HSC can promote generation of myeloid-derived suppressor cells (MDSC). HSC-induced MDSC demonstrate potent immune inhibitory activity. Induction of MDSC is dependent on an intact interferon gamma signaling pathway in HSC and is mediated by soluble factors, suggesting that the specific tissue stromal cells, such as HSC, play a crucial role in regulating immune response by way of inflammation-induced generation of MDSC. Large amounts of MDSC can be propagated in vitro from bone marrowderived myeloid precursor cells under the influence of HSC. Conclusion: Cotransplantation with in vitro generated MDSC can effectively protect islet allografts from host immune attack. Local delivery of potent immune suppressor cells for cell transplants holds great clinical application potential. (HEPATOLOGY 2011;53:1007-1019

Glucocorticoid Induces Hepatic Steatosis by Inhibiting Activating Transcription Factor 3 (ATF3)/S100A9 Protein Signaling in Granulocytic Myeloid-derived Suppressor Cells

“…Accumulation of MDSC in liver has been observed in tumor-bearing hosts, hepatitis B virus-infected individuals, and high fat dietfed animals (4,29,30). Also, hepatic stellate cells were reported to support the expansion of MDSCs in vitro (31). Our study reveals the importance of MDSCs in the modulation of lipid metabolism in liver.…”

The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells

“…9 Cotransplantation of HpSCs with islet allografts effectively protected the islet allografts from rejection without the requirement of immunosuppression via inhibition of CD8 1 T-cell responses, enhancement of regulatory T (Treg) cells, 10,11 and induction of MDSCs. 12 HpSCs have a limited capacity to directly induce Treg cells 13 but are potent inducers of MDSCs. 12 The direct link between HpSCs and MDSCs was demonstrated by addition of small amounts of HpSCs into DC (bone marrow [BM] derived) culture, leading to generation of MDSCs instead of DCs.…”

“…12 HpSCs have a limited capacity to directly induce Treg cells 13 but are potent inducers of MDSCs. 12 The direct link between HpSCs and MDSCs was demonstrated by addition of small amounts of HpSCs into DC (bone marrow [BM] derived) culture, leading to generation of MDSCs instead of DCs. These newly generated MDSCs showed potent immunosuppressive activity, and protected islet allografts as effectively as HpSCs, although the number of MDSCs required to generate the same suppressive effect as HpSCs was 10 times greater.…”

“…These newly generated MDSCs showed potent immunosuppressive activity, and protected islet allografts as effectively as HpSCs, although the number of MDSCs required to generate the same suppressive effect as HpSCs was 10 times greater. 12 To explore the molecular basis through which HpSCs promote MDSC development, HpSCs were cultured with BM cells in a transwell system. Despite the lack of direct cell contact, HpSCs were still capable of inducing MDSCs through the production of soluble factors.…”

Contact-Dependent Depletion of Hydrogen Peroxide by Catalase Is a Novel Mechanism of Myeloid-Derived Suppressor Cell Induction Operating in Human Hepatic Stellate Cells

“…In murine transplantation models, whole allogenic livers, containing a stromal cell population, engraft well, whereas hepatocytes were rejected (7,12). However, in contrast to murine HSC (13) (14), MO-MDSC induction by human HSC (15) is dependent on cell-cell contact through CD44, a glycoprotein important for monocytic chemotaxis (16), suggestive of a previously unknown mechanism of MO-MDSC induction. In this study, we show that depletion of hydrogen peroxide (H 2 O 2 ) by soluble or stromally expressed catalase drives the induction of MO-MDSC from human monocytes.…”