Notch signaling and progenitor/ductular reaction in steatohepatitis

Morell, Carola M.; Fiorotto, Romina; Meroni, Marica; Raizner, Aileen; Torsello, B; Cadamuro, Massimiliano; Spagnuolo, Gaia; Kaffe, Eleanna; Sutti, Salvatore; Albano, Emanuele; Strazzabosco, Mario

doi:10.1371/journal.pone.0187384

Cited by 24 publications

(24 citation statements)

References 36 publications

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“…DBZ, an inhibitor of Notch signaling shown to decrease DR in other mouse models of liver injury, 31,38 was then administered to CDE-fed mice. DBZ treatment significantly reduced DR extent in CDE mice ( Figure 4A).…”

Section: Dr Inhibition Correlates With Reduced Number Of Dr-canaliculmentioning

confidence: 99%

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: Dr Inhibition Correlates With Reduced Number Of Dr-canaliculmentioning

confidence: 99%

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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“…Hepatic progenitor cells have been reported to expand when tightly surrounded by both Ac‐HSCs and Ac‐HSC‐mediated ECM in diseased liver . These investigations indicate that HSCs are the niche cells for HPCs and that HSCs secrete several growth factors .…”

Section: Discussionmentioning

confidence: 96%

“…Hepatic progenitor cells have been reported to expand when tightly surrounded by both Ac-HSCs and Ac-HSCmediated ECM in diseased liver. 25,26 These investigations indicate that HSCs are the niche cells for HPCs and that HSCs secrete several growth factors. [47][48][49][50] Among these factors, HGF and fibroblast growth factor 7 (FGF7) are crucial in liver regeneration, as knockout of these molecules, but not of others, results in the failure of HPC-mediated regeneration, ultimately leading to hepatic failure and death in rodent models.…”

Section: Discussionmentioning

confidence: 99%

“…Commonly, niche cells supply several signals required for proliferation and differentiation of tissue stem cells . In the diseased liver, several experiments have revealed that HPCs expand along with the development of fibrotic septa, the production of extracellular matrix (ECM), and the activation of hepatic stellate cells (HSCs) . We sought to elucidate the role of HSCs, the main cellular component of the HPC niche, in the biology of HPCs.…”

Section: Introductionmentioning

confidence: 99%

“…23,24 In the diseased liver, several experiments have revealed that HPCs expand along with the development of fibrotic septa, the production of extracellular matrix (ECM), and the activation of hepatic stellate cells (HSCs). 25,26 We sought to elucidate the role of HSCs, the main cellular component of the HPC niche, in the biology of HPCs. We and others have reported that angiotensin II (AT-II), a component of the renin-angiotensinaldosterone system, significantly augments the proliferation of HSCs 27,28 and that an AT-II receptor type 1 blocker (ARB) significantly attenuated development of liver fibrosis in chronic liver injury in a rodent model by inhibition of HSC proliferation.…”

Section: Introductionmentioning

confidence: 99%

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Blocking development of liver fibrosis augments hepatic progenitor cell‐derived liver regeneration in a mouse chronic liver injury model

Kitade

Kaji

Nishimura

et al. 2019

Hepatology Research

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Aim The roles of hepatic progenitor cells (HPCs) in regeneration of a diseased liver are unclear. Hepatic stellate cells (HSCs) contribute to liver fibrosis but are also a component of the HPC niche. Hepatic progenitor cells expand along with HSC activation and liver fibrosis. However, little is known about the interplay of liver fibrosis and HPC‐mediated liver regeneration. This study aimed to investigate HSCs and HPCs in liver regeneration. Methods Liver injury in mice was induced with 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine, and HPC expansion and fibrosis were assessed. An angiotensin II type 1 receptor blocker (ARB) was administered to assess its effect on fibrosis and regeneration. Results Treatment with ARB attenuated fibrosis and expansion of α‐smooth muscle actin‐positive activated HSCs as indicated by increased liver weight and Ki‐67‐positive hepatocytes. Immunohistochemical staining suggested that HPC differentiation was shifted toward hepatocytes (HCs) when ARB treatment decreased HPC encapsulation by HSCs and extracellular matrix. Conditioned medium produced by culturing the human HSC LX‐2 line strongly augmented differentiation to biliary epithelial cells (BECs) but inhibited that to HCs. Activated HSCs expressed Jagged1, a NOTCH ligand, which plays a central role in differentiation of HPCs toward BECs. Conclusions Hepatic stellate cells, the HPC niche cells, control differentiation of HPCs, directing them toward BECs rather than HCs in a diseased liver model. Antifibrosis treatment with an ARB preferentially redirects HPC differentiation toward HCs by blocking the NOTCH pathway in the HPC niche, resulting in more efficient HPC‐mediated liver regeneration.

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Hepatic progenitor cell activation is induced by the depletion of the gut microbiome in mice

Wang

Sun

et al. 2019

MicrobiologyOpen

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The homeostasis of the gut microbiome is crucial for human health and for liver function. However, it has not been established whether the gut microbiome influence hepatic progenitor cells (HPCs). HPCs are capable of self‐renewal and differentiate into hepatocytes and cholangiocytes; however, HPCs are normally quiescent and are rare in adults. After sustained liver damage, a ductular reaction occurs, and the number of HPCs is substantially increased. Here, we administered five broad‐spectrum antibiotics for 14 days to deplete the gut microbiomes of male C57BL/6 mice, and we measured the plasma aminotransferases and other biochemical indices. The expression levels of two HPC markers, SRY‐related high mobility group‐box gene 9 (Sox9) and cytokeratin (CK), were also measured. The plasma aminotransferase activities were not affected, but the triglyceride, lactate dehydrogenase, low‐density lipoprotein, and high‐density lipoprotein concentrations were significantly altered; this suggests that liver function is affected by the composition of the gut microbiome. The mRNA expression of Sox9 was significantly higher in the treated mice than it was in the control mice (p < 0.0001), and a substantial expression of Sox9 and CK was observed around the bile ducts. The mRNA expression levels of proinflammatory factors (interleukin [IL]‐1β, IL‐6, tumor necrosis factor [TNF]‐α, and TNF‐like weak inducer of apoptosis [Tweak]) were also significantly higher in the antibiotic‐treated mice than the levels in the control mice. These data imply that the depletion of the gut microbiome leads to liver damage, negatively impacts the hepatic metabolism and function, and activates HPCs. However, the underlying mechanisms remain to be determined.

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Notch signaling and progenitor/ductular reaction in steatohepatitis

Cited by 24 publications

References 36 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

Blocking development of liver fibrosis augments hepatic progenitor cell‐derived liver regeneration in a mouse chronic liver injury model

Hepatic progenitor cell activation is induced by the depletion of the gut microbiome in mice

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