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: 9.86). 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND & AIMS: Proliferation of liver progenitor cells (lpcs) is associated with inflammation and fibrosis in chronic liver diseases. However, how inflammation and fibrosis affect lpcs remains obscure. METHODS: We examined the role of interferon (IFN)-γ, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- or choline-deficient, ethionine-supplemented (CDE) diet as well as in primary lpcs and LPC cell line. RESULTS: The CK19 staining scores correlated with inflammation and fibrosis grades in the livers from 110 HBV-infected patients. Nine-month IFN- γ treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN- γ treatment also decreased LPC activation in DDC-treated mice. Disruption of IFN- γ or its signaling components (eg. IFNGR, STAT1, and IRF-1) increased LPC proliferation and liver fibrosis in DDC-fed mice. In contrast, deletion of IFN- γ did not increase but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN- γ attenuated proliferation of the LPC cell line BMOL cells and of primary lpcs from wild-type mice, but not STAT1(-/-) or IRF-1(-/-) mice. Furthermore, co-culture assays suggest that IFN- γ can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells. CONCLUSION: IFN- γ inhibits LPC expansion via the direct inhibition of LPC proliferation and indirect attenuation of liver fibrosis in the DDC model but it may also enhance LPC expansion via the promotion of inflammation in the CDE model; thereby playing dual roles in regulating LPC proliferation in vivo.
    Journal of Hepatology 06/2013; · 9.86 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Hepatic progenitor cells (HPCs) are an adult stem cell compartment in the liver that contribute to liver regeneration when replication of mature hepatocytes is insufficient. In this study, laser microdissection was used to isolate HPC niches from the livers of healthy dogs and dogs with lobular dissecting hepatitis (LDH), in which HPCs are massively activated. Gene expression of HPC, hepatocyte and biliary markers was determined by quantitative reverse transcriptase PCR. Expression and localisation of selected markers were further studied at the protein level by immunohistochemistry and immunofluorescent double staining in samples of normal liver and liver from dogs with LDH, acute and chronic hepatitis, and extrahepatic cholestasis. Activated HPC niches had higher mRNA expression of the hepatic progenitor markers OPN, FN14, CD29, CD44, CD133, LIF, LIFR and BMI1 compared to HPCs from normal liver. There was lower expression of albumin, but activated HPC niches were positive for the biliary markers SOX9, HNF1β and keratin 19 by immunohistochemistry and immunofluorescence. Laminin, activated stellate cells and macrophages are abundant extracellular matrix and cellular components of the canine HPC niche. This study demonstrates that the molecular and cellular characteristics of canine HPCs are similar to rodent and human HPCs, and that canine HPCs are distinctively activated in different types of liver disease.
    The Veterinary Journal. 01/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Morphostasis (tissue homeostasis) is a complex process consisting of three circumstances: (1) tissue renewal from stem cells, (2) preservation of tissue cells in a proper differentiated state and (3) maintenance of tissue quantity. This can be executed by a tissue control system (TCS) consisting of vascular pericytes, immune system-related components--monocyte-derived cells (MDC), T cells and immunoglobulins and autonomic innervation. Morphostasis is established epigenetically, during the critical developmental period corresponding to the morphogenetic immune adaptation. Subsequently, the tissues are maintained in a state of differentiation reached during the adaptation by a 'stop effect' of MDC influencing markers of differentiating tissue cells and presenting self-antigens to T cells. Retardation or acceleration of certain tissue differentiation during adaptation results in its persistent functional immaturity or premature ageing. The tissues being absent during adaptation, like ovarian corpus luteum, are handled as a 'graft.' Morphostasis is altered with age advancement, because of the degenerative changes of the immune system. That is why the ageing of individuals and increased incidence of neoplasia and degenerative diseases occur. Hybridization of tumour stem cells with normal tissue cells causes an augmentation of neoplasia by host pericytes and MDC stimulating a 'regeneration' of depleted functional cells. Degenerative diseases are associated with apoptosis. If we are able to change morphostasis in particular tissue, we may disrupt apoptotic process of the cell. An ability to manage the 'stop effect' of MDC may provide treatment for early post-natal tissue disorders, improve regenerative medicine and delay physical, mental and hormonal ageing.
    Scandinavian Journal of Immunology 03/2011; 73(3):159-89. · 2.20 Impact Factor

Full-text (2 Sources)

Available from
May 30, 2014