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


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.
    Journal of Hepatology 04/2015; 63(3). DOI:10.1016/j.jhep.2015.04.003 · 11.34 Impact Factor
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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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    ABSTRACT: Normal tissue architecture is disrupted following injury, as resident tissue cells become damaged and immune cells are recruited to the site of injury. While injury and inflammation are critical to tissue remodeling, the inability to resolve this response can lead to the destructive complications of chronic inflammation. In the pancreas, acinar cells of the exocrine compartment respond to injury by transiently adopting characteristics of progenitor cells present during embryonic development. This process of de-differentiation creates a window where a mature and stable cell gains flexibility and is potentially permissive to changes in cellular fate. How de-differentiation can turn an acinar cell into another cell type (such as a pancreatic β-cell), or a cell with cancerous potential (as in cases of deregulated Kras activity) is of interest to both the regenerative medicine and cancer communities. While it is known that inflammation and acinar de-differentiation increase following pancreatic injury, it remains unclear which immune cells are involved in this process. We used a combination of genetically modified mice, immunological blockade and cellular characterization to identify the immune cells that impact pancreatic regeneration in an in vivo model of pancreatitis. We identified the innate inflammatory response of macrophages and neutrophils as regulators of pancreatic regeneration. Under normal conditions, mild innate inflammation prompts a transient de-differentiation of acinar cells that readily dissipates to allow normal regeneration. However, non-resolving inflammation developed when elevated pancreatic levels of neutrophils producing interferon-γ increased iNOS levels and the pro-inflammatory response of macrophages. Pancreatic injury improved following in vivo macrophage depletion, iNOS inhibition as well as suppression of iNOS levels in macrophages via interferon-γ blockade, supporting the impairment in regeneration and the development of chronic inflammation arises from aberrant activation of the innate inflammatory response. Collectively these studies identify targetable inflammatory factors that can be used to influence the development of non-resolving inflammation and pancreatic regeneration following injury.
    PLoS ONE 07/2014; 9(7):e102125. DOI:10.1371/journal.pone.0102125 · 3.23 Impact Factor
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    • "Cytokines (e.g. TWEAK) produced by this inflammatory cell can modulate HPC behavior over large distances in the tissue [77,78]. HPC migration through the parenchyma was significantly decreased in mice depleted for macrophages with clodronate and subsequently subjected to liver injury [79]. "
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    ABSTRACT: New curative therapies for severe liver disease are urgently needed in both the human and veterinary clinic. It is important to find new treatment modalities which aim to compensate for the loss of parenchymal tissue and to repopulate the liver with healthy hepatocytes. A prime focus in regenerative medicine of the liver is the use of adult liver stem cells, or hepatic progenitor cells (HPCs), for functional recovery of liver disease. This review describes recent developments in HPC research in dog and cat and compares these findings to experimental rodent studies and human pathology. Specifically, the role of HPCs in liver regeneration, key components of the HPC niche, and HPC activation in specific types of canine and feline liver disease will be reviewed. Finally, the potential applications of HPCs in regenerative medicine of the liver are discussed and a potential role is suggested for dogs as first target species for HPC-based trials.
    BMC Veterinary Research 06/2014; 10(1):137. DOI:10.1186/1746-6148-10-137 · 1.78 Impact Factor
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