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. 2017 Sep;1(2):81-87.
doi: 10.1016/j.livres.2017.08.002. Epub 2017 Aug 9.

Hepatic progenitor cell activation in liver repair

Adam Bria  1 , Jorgessen Marda  1 , Junmei Zhou  1 , Xiaowei Sun  1 , Qi Cao  1 , Bryon E Petersen  1 , Liya Pi  1
Affiliations

Hepatic progenitor cell activation in liver repair

Adam Bria et al. Liver Res. 2017 Sep.

Abstract

The liver possesses an extraordinary ability to regenerate after injury. Hepatocyte-driven liver regeneration is the default pathway in response to mild-to-moderate acute liver damage. When replication of mature hepatocytes is blocked, facultative hepatic progenitor cells (HPCs), also referred to as oval cells (OCs) in rodents, are activated. HPC/OCs have the ability to proliferate clonogenically and differentiate into several lineages including hepatocytes and bile ductal epithelia. This is a conserved liver injury response that has been studied in many species ranging from mammals (rat, mouse, and human) to fish. In addition, improper HPC/OC activation is closely associated with fibrotic responses, characterized by myofibroblast activation and extracellular matrix production, in many chronic liver diseases. Matrix remodeling and metalloprotease activities play an important role in the regulation of HPC/OC proliferation and fibrosis progression. Thus, understanding molecular mechanisms underlying HPC/OC activation has therapeutic implications for rational design of anti-fibrotic therapies.

Keywords: Hepatic fibrosis; Hepatic progenitor cells (HPCs); Liver injury; Liver regeneration; Oval cells (OCs).

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Conflict of interest statement

Conflict of interest The authors declare that they have no conflict of interest.

Figures

Fig.1
Fig.1
Comparison of AA- or CCl4- induced liver fibrosis in rats. AA (7.4 mg/kg) and CCl4 (300 mg/kg) were given to rats through IP injection for 90 days to induce chronic injury based on previous reports., H&E, αSMA and Trichrome staining were carried out. Damaged and fibrotic areas (indicated by arrows or arrowheads) are shown.
Fig. 2
Fig. 2. AA or CCl4 administration causes periportal or central lobular proliferation, respectively
AA (7.4 mg/kg) and CCl4 (300 mg/kg) were administered to rats through IP injection for 45 days. BrdU (100 mg/kg body weight) was injected into animals 2 hours before sacrifice. H&E staining was performed to monitor histological changes in damaged livers. Proliferating cells were labeled with monoclonal mouse BrdU antibody followed by 3, 3’-diaminobenzidine (DAB) detection. Arrowheads indicate proliferating cells and damaged areas. Scale bar: 100 µm. PV: portal vein; CV: central vein.
Fig.3
Fig.3. HPC/OC niche and its damage responses
(A) The HPC/OC niche consists of a specialized pro-fibrogenic extracellular matrix, epithelial elements (hepatocytes, cholangiocytes and their intermediate state), inflammatory cells, and myofibroblasts. Based on the type of injury, HPC/OCs can differentiate into either hepatocytes or bile ductular epithelial cells. Phagocytosis of hepatocyte debris by liver macrophages results in expression of Wnt3a. Wnt3a in close proximity to HPC/OCs activates Wnt pathways, leading to transcriptional activation of Numb (a Notch pathway inhibitor) and progenitor differentiation into hepatocytes. In biliary injury, HPC/OC activation in the form of a ductular reaction is often associated with myofibroblast activation and extensive collagen deposition, leading to liver fibrosis. Myofibroblasts express Jagged1 that activates Notch receptors in HPC/OCs leading to differentiation towards a biliary lineage. (B) CTGF/CCN2 acts in an autocrine manner to promote HPC/OC activation, ductular reaction and biliary fibrosis by binding to the integrin αvβ6 receptor on HPC/OCs and cholangiocytes in DDC-induced murine liver injury. ADAMTS7 protease can be secreted from hepatocytes and myofibroblasts in the HPC/OC niche to regulate HPC/OC activation and biliary fibrosis by CTGF/CCN2 fragmentation.
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