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.

Download full-text


Available from: Kay Samuel
  • Source
    • "Therefore, to overcome variability, and in an effort to define our differentiation process, we employed two recombinant full-length human laminins and compared those with Matrigel in three hESC lines, two of which are available at GMP-grade. The laminins used in our system were selected because of their importance in the developing embryo (Domogatskaya et al., 2012; Miner et al., 2004), the regenerating liver (Martinez-Hernandez and Amenta, 1995; Carlsson et al., 1981), and the liver stem cell niche (Tanimizu et al., 2012; Lorenzini et al., 2010). Additionally, the laminins employed in this study are known to support the clonal expansion of hESCs (Rodin et al., 2010) and drive endodermal differentiation (Taylor-Weiner et al., 2013) and liver stem cell differentiation (Takayama et al., 2013a), making them ideal candidate substrates for our purposes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stem cell-derived somatic cells represent an unlimited resource for basic and translational science. Although promising, there are significant hurdles that must be overcome. Our focus is on the generation of the major cell type of the human liver, the hepatocyte. Current protocols produce variable populations of hepatocytes that are the product of using undefined components in the differentiation process. This serves as a significant barrier to scale-up and application. To tackle this issue, we designed a defined differentiation process using recombinant laminin substrates to provide instruction. We demonstrate efficient hepatocyte specification, cell organization, and significant improvements in cell function and phenotype. This is driven in part by the suppression of unfavorable gene regulatory networks that control cell proliferation and migration, pluripotent stem cell self-renewal, and fibroblast and colon specification. We believe that this represents a significant advance, moving stem cell-based hepatocytes closer toward biomedical application.
    Full-text · Article · Nov 2015 · Stem Cell Reports
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jun 2014 · BMC Veterinary Research
  • Source
    • "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 "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Apr 2014 · Middle East journal of digestive diseases
Show more