Reactive cholangiocytes differentiate into proliferative hepatocytes with efficient DNA repair in mice with chronic liver injury

Manco, Rita; Clerbaux, Laure-Alix; Verhulst, Stefaan; Nader, Myriam Bou; Sempoux, Christine; Ambroise, Jérôme; Bearzatto, Bertrand; Gala, Jean Luc; Horsmans, Yves; Grunsven, Leo A. van; Desdouets, Chantal; Leclercq, Isabelle

doi:10.1016/j.jhep.2019.02.003

Cited by 64 publications

(72 citation statements)

References 46 publications

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“…tamoxifen-injected osteopontin-iCreER T2 ;Rosa26-YFP mice were used as a genetic tool to trace approximately 90% of cholangiocytes. 22,37 On CDE diet, a large bulk of DR cells was YFP þ and interestingly all of the mucin þ cells engaged in a junction were YFP þ , meaning that they derived from preexisting biliary cells, further confirming that DRs expand from the biliary tree ( Figure 3A). Furthermore, as already described in CDE livers, YFP expression is also found in a limited number of hepatocytes that have differentiated from biliary/DR cells.…”

Section: Invasive Biliary Dr Establishes New Junctions With Intralobumentioning

confidence: 76%

Invasive Ductular Reaction Operates Hepatobiliary Junctions upon Hepatocellular Injury in Rodents and Humans

Clerbaux

Manco

Hul

et al. 2019

The American Journal of Pathology

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Ductular reaction (DR) is observed in virtually all liver diseases in both humans and rodents. Depending on the injury, DR is confined within the periportal area or invades the parenchyma. On severe hepatocellular injury, invasive DR has been proposed to arise for supplying the liver with new hepatocytes. However, experimental data evidenced that DR contribution to hepatocyte repopulation is at the most modest, unless replicative capacity of hepatocytes is abrogated. Herein, we proposed that invasive DR could contribute to operating hepatobiliary junctions on hepatocellular injury. The choline-deficient ethionine-supplemented mouse model of hepatocellular injury and human liver samples were used to evaluate the hepatobiliary junctional role of the invasive form of DR. Choline-deficient ethioninesupplementedeinduced DR expanded as biliary epithelium into the lobule and established new junctions with the canaliculi. By contrast, no new ductular-canalicular junctions were observed in mouse models of biliary obstructive injury exhibiting noninvasive DR. Similarly, in humans, an increased number of hepatobiliary junctions were observed in hepatocellular diseases (viral, drug induced, or metabolic) in whichThe biliary tree is an arborizing network of conduits that drains bile secreted by hepatocytes to the gut. Bile secretion is an active and tightly regulated process resulting in extrusion of biliary components at the apical pole of hepatocytes into a space sealed by tight junctions between adjacent hepatocytes, the canaliculus. Coordinated contractions of the pericanalicular microfilaments drain bile downstream to bile ductules delineated by cholangiocytes enclosed in the portal mesenchyme. The canal of Hering (CoH), a transitional structure formed by the apical poles of hepatocytes in the periportal region and by cholangiocytes of the most proximal extremities of the bile ductules, represents the anatomic interface between the canaliculi and the ducts. 1 Small ductules converge to form larger ducts, then carry the bile to the gallbladder and the gut. 2 The morphology and functional properties of cholangiocytes vary gradually along the proximal to distal axis. 3e5 Cholestasis may be caused by a large variety of structural or functional insults that can occur at any level between the hepatocytes and the ampulla of Vater, which results in

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Section: Invasive Biliary Dr Establishes New Junctions With Intralobumentioning

confidence: 76%

Invasive Ductular Reaction Operates Hepatobiliary Junctions upon Hepatocellular Injury in Rodents and Humans

Clerbaux

Manco

Hul

et al. 2019

The American Journal of Pathology

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“…To model human liver diseases caused by severe injury, recent studies have combined the classical chemically induced liver injury model with either extended duration of injury [37,38] or genetic manipulation to inhibit the proliferation of hepatocytes [39,40]. Strikingly, by labeling biliary Trends Trends in in Cell Biology Cell Biology Figure 2.…”

Section: Biliary Epithelial Cell Plasticity In Injury-induced Regenermentioning

confidence: 99%

Cell Plasticity in Liver Regeneration

Hui

2020

Trends in Cell Biology

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The liver, whose major functional cell type is the hepatocyte, is a peculiar organ with remarkable regenerative capacity. The widely held notion that hepatic progenitor cells contribute to injury-induced liver regeneration has long been debated. However, multiple lines of evidence suggest that the plasticity of differentiated cells is a major mechanism for the cell source in injury-induced liver regeneration. Investigating cell plasticity could potentially expand our understanding of liver physiology and facilitate the development of new therapies for liver diseases. In this review, we summarize the cell sources for hepatocyte regeneration and the clinical relevance of cell plasticity for human liver diseases. We focus on mechanistic insights on the injury-induced cell plasticity of hepatocytes and biliary epithelial cells and discuss future directions for investigation. Specifically, we propose the notion of 'reprogramming competence' to explain the plasticity of differentiated hepatocytes. Liver Regeneration and Cell PlasticityThe liver harbors remarkable regenerative capacity and performs multiple physiological functions [1,2]. However, as this organ is central for metabolism and detoxification, it often suffers extraneous injury and gradually loses its regenerative ability [1,2]. Understanding the mechanisms of liver regeneration is a fundamental topic in liver biology. Since hepatocytes are the primary effector cells for liver physiological functions, the cell source for new hepatocytes after injury has been a main focus in liver regeneration research. It has long been debated whether stem cells contribute to injury-induced liver regeneration. However, recent studies have shown that cell sources other than stem cells also contribute to injury-induced liver regeneration [3]. Cell reprogrammingthat is, the plasticity of hepatocytes and biliary epithelial cellshas been identified as a major pathway to generate new hepatocytes in response to liver injury. Therefore, a better understanding of the underlying mechanisms of injury-induced cell plasticity in vivo may facilitate the development of cell-plasticitybased therapies. In this review, we summarize the latest findings on cell sources with mechanistic regulation in liver regeneration and discuss their clinical relevance to human liver diseases. Liver Homeostasis under Physiological ConditionsIt has long been proposed that the liver harbors liver progenitor cells (LPCs) in the canal of Hering, a structure that connects bile canaliculi with bile ducts in periportal areas, to fulfil liver regeneration requirements under normal physiological conditions [2]. LPCs are characterized based on the following properties: (i) clonogenic ability with high proliferation potential; (ii) the ability to differentiate into both hepatocytes and cholangiocytes under culture conditions; and (iii) liver repopulation ability after transplantation [2]. The 'streaming liver' model was proposed decades ago to describe the contribution of LPCs to in vivo liver homeostasis. This model de...

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“…The present study 13 adds to the evidence for the role of biliary-derived hepatocytes in restoration of the liver parenchyma following chronic liver injury. The authors rely on mice with an inducible Osteopontin-iCreER T2 allele to label biliary cells with several different marker genes -YFP, mT/mG or confetti.…”

mentioning

confidence: 57%

Biliary-derived hepatocytes in chronic liver injury: Bringing new troops to the battlefield?

Aleksieva

Forbes²

2019

Journal of Hepatology

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Reactive cholangiocytes differentiate into proliferative hepatocytes with efficient DNA repair in mice with chronic liver injury

Cited by 64 publications

References 46 publications

Invasive Ductular Reaction Operates Hepatobiliary Junctions upon Hepatocellular Injury in Rodents and Humans

Invasive Ductular Reaction Operates Hepatobiliary Junctions upon Hepatocellular Injury in Rodents and Humans

Cell Plasticity in Liver Regeneration

Biliary-derived hepatocytes in chronic liver injury: Bringing new troops to the battlefield?

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