Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver

MRC/University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, UK.
Gut (Impact Factor: 14.66). 05/2010; 59(5):645-54. DOI: 10.1136/gut.2009.182345
Source: PubMed


Stem/progenitor cell niches in tissues regulate stem/progenitor cell differentiation and proliferation through local signalling.
To examine the composition and formation of stem progenitor cell niches.
The composition of the hepatic progenitor cell niche in independent models of liver injury and hepatic progenitor cell activation in rodents and humans was studied. To identify the origin of the progenitor and niche cells, sex-mismatched bone marrow transplants in mice, who had received the choline-ethionine-deficient-diet to induce liver injury and progenitor cell activation, were used. The matrix surrounding the progenitor cells was described by immunohistochemical staining and its functional role controlling progenitor cell behaviour was studied in cell culture experiments using different matrix layers.
The progenitor cell response in liver injury is intimately surrounded by myofibroblasts and macrophages, and to a lesser extent by endothelial cells. Hepatic progenitor cells are not of bone marrow origin; however, bone marrow-derived cells associate intimately with these cells and are macrophages. Laminin always surrounds the progenitor cells. In vitro studies showed that laminin aids maintenance of progenitor and biliary cell phenotype and promotes their gene expression (Dlk1, Aquaporin 1, gammaGT) while inhibiting hepatocyte differentiation and gene expression (CEPB/alpha).
During liver damage in rodents and humans a stereotypical cellular and laminin niche forms around hepatic progenitor cells. Laminin helps maintenance of undifferentiated progenitor cells. The niche links the intrahepatic progenitor cells with bone marrow-derived cells and links tissue damage with progenitor cell-mediated tissue repair.

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    • "The deposition and remodeling of laminin is required for HPC proliferation and migration and it maintains the undifferentiated state of the HPCs. It is only when the HPCs ‘escape’ from the laminin matrix and enter the parenchyma that differentiation occurs [44,81,82]. HPCs express markers such as CD29 and CD44, clearly indicating that they have the molecular make-up to communicate with their ECM [59,83]. "
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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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    • "The significance of cross-talk between ECM components and oval cells/HPCs in the expansion and differentiation of these cells has also been suggested by other groups.55,56 In a wide variety of human chronic liver diseases, HPCs and ECM producing activated hepatic stellate cells/myofibroblasts appear to proliferate in close proximity to each other and correlate in terms of numbers.37,57,58 Recently, it has been shown that in patients with chronic hepatitis B and C, HPCs co-localize with laminin, endothelial cells, myofibroblasts and macrophages.37 "
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    ABSTRACT: The hepatic progenitor cell (HPC) niche is a special microenvironment composed of different cell types, extracellular matrix (ECM) components, growth factors and cytokines released by the niche cells that help to maintain the characteristics of HPCs and the balance between their activation, proliferation and differentiation. Composition of this special microenvironment, created in response to specific liver damage, together with critical interactions between different partners of the HPC niche can determine the fate decision and differentiation pathways of HPCs. A number of recent studies have shed light on factors and signals from the HPC niche that determines the choice of HPCs differentiation towards a specific cell type depending on the nature of the liver injury and resultant microenvironment created by this injury. This paper seeks to provide an in-depth review, through a literature review and the authors' experiences, of the most recent findings on the role of the HPC niche in fate choice option of HPCs toward either hepatocytes or bile duct epithelial cells and its clinical relevance.
    Middle East journal of digestive diseases 04/2014; 6(2):57-64.
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    • "The similarity of these Dlk1-positive HPCs with fetal hepatocytes might indicate the presence of a cellular hierarchy in the HPC response. Therefore, this and previous studies document laminin [2,3,6] and Collagen1 [15] deposition around HPCs, suggesting an important role for these components in the HPC response. Interestingly, in in vitro studies, opposed roles for laminin and Collagen1 with respect to HPCs have been observed. "
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    ABSTRACT: Tissue repair in the adult mammalian liver occurs in two distinct processes, referred to as the first and second tiers of defense. We undertook to characterize the changes in molecular constituents of the extracellular matrix when hepatic progenitor cells (HPCs) respond in a second tier of defense to liver injury. We used transcriptional profiling on rat livers responding by a first tier (surgical removal of 70 % of the liver mass (PHx protocol)) and a second tier (70 % hepatectomy combined with exposure to 2-acetylaminofluorene (AAF/PHx protocol)) of defense to liver injury and compared the transcriptional signatures in untreated rat liver (control) with those from livers of day 1, day 5 and day 9 post hepatectomy in both protocols. Numerous transcripts encoding specific subunits of collagens, laminins, integrins, and various other extracellular matrix structural components were differentially up- or down-modulated (P < 0.01). The levels of a number of transcripts were significantly up-modulated, mainly in the second tier of defense (Agrn, Bgn, Fbn1, Col4a1, Col8a1, Col9a3, Lama5, Lamb1, Lamb2, Itga4, Igtb2, Itgb4, Itgb6, Nid2), and their signal intensities showed a strong or very strong correlation with Krt1-19, a well-established marker of a ductular/HPC reaction. Furthermore, a significant up-modulation and very strong correlation between the transcriptional profiles of Krt1-19 and St14 encoding matriptase, a component of a novel protease system, was found in the second tier of defense. Real-time PCR confirmed the modulation of St14 transcript levels and strong correlation to Krt-19 and also showed a significant up-modulation and strong correlation to Spint1 encoding HAI-1, a cognate inhibitor of matriptase. Immunodetection and three-dimensional reconstructions showed that laminin, Collagen1a1, agrin and nidogen1 surrounded bile ducts, proliferating cholangiocytes, and HPCs in ductular reactions regardless of the nature of defense. Similarly, matriptase and HAI-1 were expressed in cholangiocytes regardless of the tier of defense, but in the second tier of defense, a subpopulation of HPCs in ductular reactions co-expressed HAI-1 and the fetal hepatocyte marker Dlk1. Transcriptional profiling and immunodetection, including three-dimensional reconstruction, generated a detailed overview of the extracellular matrix constituents expressed in a second tier of defense to liver injury.
    Fibrogenesis & Tissue Repair 12/2013; 6(1):21. DOI:10.1186/1755-1536-6-21
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