Stem Cells and Liver Regeneration

Oregon Stem Cell Center, Oregon Health & Science University, Portland, Oregon 97239-3098, USA.
Gastroenterology (Impact Factor: 13.93). 06/2009; 137(2):466-81. DOI: 10.1053/j.gastro.2009.05.044
Source: PubMed

ABSTRACT One of the defining features of the liver is the capacity to maintain a constant size despite injury. Although the precise molecular signals involved in the maintenance of liver size are not completely known, it is clear that the liver delicately balances regeneration with overgrowth. Mammals, for example, can survive surgical removal of up to 75% of the total liver mass. Within 1 week after liver resection, the total number of liver cells is restored. Moreover, liver overgrowth can be induced by a variety of signals, including hepatocyte growth factor or peroxisome proliferators; the liver quickly returns to its normal size when the proliferative signal is removed. The extent to which liver stem cells mediate liver regeneration has been hotly debated. One of the primary reasons for this controversy is the use of multiple definitions for the hepatic stem cell. Definitions for the liver stem cell include the following: (1) cells responsible for normal tissue turnover, (2) cells that give rise to regeneration after partial hepatectomy, (3) cells responsible for progenitor-dependent regeneration, (4) cells that produce hepatocyte and bile duct epithelial phenotypes in vitro, and (5) transplantable liver-repopulating cells. This review will consider liver stem cells in the context of each definition.

Download full-text


Available from: Markus Grompe, Jun 12, 2015
  • Source
    • "The liver is mainly composed of two epithelial cell types, hepatocytes and ductal cells. Hepatocytes synthesize essential serum proteins, control metabolism, and detoxify a wide variety of endogenous and exogenous molecules (Duncan et al., 2009). Despite their considerable replication capacity in vivo (Michalopoulos, 2014), hepatocytes have resisted long-term expansion in culture (Mitaka, 1998). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Despite the enormous replication potential of the human liver, there are currently no culture systems available that sustain hepatocyte replication and/or function in vitro. We have shown previously that single mouse Lgr5+ liver stem cells can be expanded as epithelial organoids in vitro and can be differentiated into functional hepatocytes in vitro and in vivo. We now describe conditions allowing long-term expansion of adult bile duct-derived bipotent progenitor cells from human liver. The expanded cells are highly stable at the chromosome and structural level, while single base changes occur at very low rates. The cells can readily be converted into functional hepatocytes in vitro and upon transplantation in vivo. Organoids from α1-antitrypsin deficiency and Alagille syndrome patients mirror the in vivo pathology. Clonal long-term expansion of primary adult liver stem cells opens up experimental avenues for disease modeling, toxicology studies, regenerative medicine, and gene therapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell 01/2015; 160(1-2):299-312. DOI:10.1016/j.cell.2014.11.050 · 33.12 Impact Factor
  • Source
    • "Liver stem cells (LSCs) have long been favored as the most likely alternative source of hepatocytes in the adult liver. In the classical view, LSCs are nonhepatocyte precursors of highly proliferative progenitor cells that can differentiate into both hepatocytes and biliary epithelial cells (BECs), thereby providing a backup system for liver regeneration (Duncan et al., 2009). In support of this view, cells that are bipotential in vitro can be isolated from the adult mouse liver (Dorrell et al., 2011; Huch et al., 2013; Shin et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatocytes provide most liver functions, but they can also proliferate and regenerate the liver after injury. However, under some liver injury conditions, particularly chronic liver injury where hepatocyte proliferation is impaired, liver stem cells (LSCs) are thought to replenish lost hepatocytes. Conflicting results have been reported about the identity of LSCs and their contribution to liver regeneration. To address this uncertainty, we followed candidate LSC populations by genetic fate tracing in adult mice with chronic liver injury due to a choline-deficient, ethionine-supplemented diet. In contrast to previous studies, we failed to detect hepatocytes derived from biliary epithelial cells or mesenchymal liver cells beyond a negligible frequency. In fact, we failed to detect hepatocytes that were not derived from pre-existing hepatocytes. In conclusion, our findings argue against LSCs, or other nonhepatocyte cell types, providing a backup system for hepatocyte regeneration in this common mouse model of chronic liver injury.
    Cell Reports 08/2014; 8(5). DOI:10.1016/j.celrep.2014.07.003 · 8.36 Impact Factor
  • Source
    • "These multipotent cells are derived from the embryonic cells of the ductal plate. The cells are identified from their expression of progenitor markers: claudin 3, neural cell adhesion molecule (NCAM), or hematopoietic, endothelial, or mesenchymal cell markers , which are not found on hepatoblasts [12]. These cells are located in stem cell niches in the Canals of Hering, anatomically juxtaposed between the intralobular canalicular system of hepatocytes and the biliary tree [29]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alcoholic liver disease affects a great number of people worldwide. With limited therapeutic options, stem cell therapy offers significant potential for these patients. To date, a limited number of clinical trials have produced transient clinical responses to cell therapy in patients with alcoholic liver disease. Stem cell therapy to reorganize the postnatal liver is an important theme and mission for patients with chronic liver disorders including alcoholic liver injury. We therefore should redevelop the evidence of cell-based liver regeneration therapy, focusing on targets (disease, patient's status and hepatic function), materials (cells, cytokines and genes), and methodology (stem cell types and their derived microparticles, transplantation route, implantation technology and tissue engineering). In this review, we summarize the recent findings regarding the experimental and clinical use of mesenchymal and liver stem cells, focusing mainly on the treatment of alcoholic liver disorders and their relevance in the field of regenerative medicine, and advances on the role of microvesicles and exosomes in this process. We discuss new advances in stem cell therapy from liver regeneration to liver re-organization, which is involved in the recent progress of on-going clinical trials, basic research in stem cell therapy and liver regeneration, and updated exosomes/microvesicles recovery/repairing technology.
    Digestive and Liver Disease 01/2014; 46(5). DOI:10.1016/j.dld.2013.11.015 · 2.89 Impact Factor
Show more