Article

Invading macrophages play a major role in the liver progenitor cell response to chronic liver injury

School of Biomedical, Biomolecular and Chemical Sciences, The University of Western Australia, Australia.
Journal of Hepatology (Impact Factor: 11.34). 09/2010; 53(3):500-7. DOI: 10.1016/j.jhep.2010.04.010
Source: PubMed

ABSTRACT

Although a strong association between liver progenitor cells (LPCs) and inflammation exists in many chronic liver diseases, the exact role of the immune system in LPC-mediated hepatic regeneration remains unclear. A number of pro-inflammatory factors were identified in cytokine knockout mice in which the LPC response was attenuated but neither the mechanism nor the producing cells are known.
To identify the critical immune cells and cytokines required in the LPC response, we compared two diet-induced models of liver injury with two recently established transgenic models of immune-mediated hepatitis.
Despite severe inflammation being observed in all models, the generation of LPCs was highly dependent on the cause and kinetics of liver damage. The LPC response was associated with an increase of macrophages and CD8(+) T cells but not natural killer cells. T cell-deficient mice were able to mount a LPC response, albeit delayed, suggesting that T cells are not essential. Mice mounting an LPC response showed elevated numbers of Kupffer cells and invading CX(3)CR1(high)CCR2(high) macrophages secreting persistent high levels of tumour necrosis factor alpha (TNFalpha), a major cytokine involved in the LPC response.
Liver macrophages are an important determinant of LPC expansion during liver regeneration in models of diet- and immune-mediated liver injury. Invading macrophages in particular provide pro-mitogenic cytokines such as TNFalpha that underpin the process. LPC themselves are a source of chemokines (CCL2, CX(3)CL1) that attract infiltrating macrophages.

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    • "In addition, patients with AH were characterized by a significantly higher total K7 liver positivity calculated by morphometric analysis compared to controls (Fig. 1B). Taken together, these results emphasize the association between Kupffer cell and LPC expansion in AH, as previously reported in experimental chronic liver injury [33]. Double immunostaining for K7 and Ki67 was used to quantify proliferating LPC (double K7 + /Ki67 + cells) or proliferating hepatocytes (large Ki67 + , K7 À cells). "
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    ABSTRACT: The role of liver progenitor cell (LPC) expansion, known as a marker of disease severity, as well as the impact of macrophage activation on liver regeneration remains unclear in humans. We aimed to characterize the LPC and macrophage compartments in alcoholic hepatitis (AH), as well as gene expression patterns predictors of a good prognosis in this setting. Immunohistochemical studies for macrophages, proliferative hepatocytes, total and proliferative LPC as well as whole liver microarray gene expression were performed on baseline liver biopsies of 58 AH patients early after admission. Abstinent cirrhotics were used as controls. Patients were qualified as "improvers" or "non-improvers" based on the change in MELD score 3 months after baseline. Compared to controls, AH patients demonstrated a significant expansion of macrophages, invasion of LPC and a higher number of proliferating hepatocytes and LPC. In AH patients, total LPC expansion (total Keratin7(+) cells) was associated with liver disease severity. The group of improvers(n=34) was characterized at baseline by a higher number of proliferating hepatocytes, proliferative LPC (double Keratin7(+)Ki67(+) cells) and liver macrophages as compared tonon-improvers (n=24), despite similar clinical and biological variables. Up-regulated genes in improvers were associated with cell cycle mitosis together with a major expression of SPINK1. Higher liver macrophage expansion, increased proliferative hepatocyte but also LPC number as well as up-regulation of cell proliferation related genes are associated with a favourable outcome. Those new findings open novel therapeutic targets in AH. Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Apr 2015 · Journal of Hepatology
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    • "Dynamic cell signalling in this niche controls self-renewal and differentiation of stem cells (Fuchs et al., 2004). Activation of hepatic stellate cells and macrophages, which play a pivotal role in hepatitis, are involved in activation of the HPC compartment (Roskams, 2008;Viebahn et al., 2010;Boulter et al., 2012). HPCs have been identified in the canine liver (Yoshioka et al., 2004;Mekonnen et al., 2007;Arends et al., 2009a and b;Schotanus et al., 2009;Ijzer et al., 2010), but HPCs and the HPC niche have not been characterised in detail. "
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    • "Tissue injury is a destructive process that creates cellular disorganization and an influx of immunological cells and factors [1], [2]. The inflammation generated in response to injury can increase cellular flexibility and promote tissue renewal by influencing tissue outgrowth, branching, organization and remodeling [2]–[6]. However, failure to resolve acute inflammation following injury can lead to the development of the chronic inflammation that contributes to the pathogenesis of several diseases [4], [7], [8]. "
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