Injury to peribiliary glands and vascular plexus before liver transplantation predicts formation of non-anastomotic biliary strictures

Dries, Sanna op den; Westerkamp, Andrie C.; Karimian, Negin; Gouw, Annette S.H.; Bruinsma, Bote G.; Markmann, James F.; Lisman, Ton; Yeh, Heidi; Uygun, Korkut; Martins, Paulo Ney Aguiar; Porte, Robert J.

doi:10.1016/j.jhep.2014.02.010

Cited by 165 publications

(191 citation statements)

References 30 publications

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“…This observation has led to the hypothesis that insufficient proliferation and regeneration of cholangiocytes from the peribiliary glands are important factors in the pathogenesis of NAS. 3,4 In the current study, we did not observe differences in injury of the peribiliary glands between the groups with end-ischemic MP and only SCS preservation. These findings are in contrast with our histological study in human donor livers demonstrating substantial injury of the more peripheral layers of the bile duct wall, including the peribiliary biliary glands, after SCS preservation.…”

Section: Discussioncontrasting

confidence: 51%

“…These findings are in contrast with our histological study in human donor livers demonstrating substantial injury of the more peripheral layers of the bile duct wall, including the peribiliary biliary glands, after SCS preservation. 4 This study indicated that the severity of bile duct injury decreases from the most central, periluminal layers toward the periphery of the bile ducts. 4 This is compatible with the fact that blood supply to the bile ducts enters from the periphery, resulting in the lowest oxygen tension in central structures situated near the lumen.…”

Section: Discussionmentioning

confidence: 68%

“…4 This study indicated that the severity of bile duct injury decreases from the most central, periluminal layers toward the periphery of the bile ducts. 4 This is compatible with the fact that blood supply to the bile ducts enters from the periphery, resulting in the lowest oxygen tension in central structures situated near the lumen. Peribiliary glands are situated in the peripheral layers of the bile duct wall.…”

Section: Discussionmentioning

confidence: 68%

“…Recently, 3 independent clinical studies have demonstrated that major mucosal cell loss (>50% biliary epithelial injury) and mural stroma necrosis (<50% necrotic cells) of the large bile duct is present in more than 80% of human donor livers (both DBD and DCD) at the end of SCS and subsequent reperfusion. 4,24,27 Although biliary preservation injury is apparently almost universally present, only a minority ) concentration and pH detected in bile. Biliary bicarbonate concentrations were significantly higher in livers that had been preserved by end-ischemic HMP, COR, or SNMP compared to livers that underwent only SCS (*P < 0.05).…”

Section: Discussionmentioning

confidence: 99%

“…2 The combination of ischemia and I/R injury can lead to impaired regeneration of the biliary epithelium with latter NAS formation as clinical consequence. 3,4 A short period of end-ischemic machine perfusion (MP) after the regular period of static cold storage (SCS) has been shown to reduce I/R injury, compared to SCS alone. 5 Although the exact mechanisms underlying the protective effects of end-ischemic MP are not fully known, an important feature of endischemic MP is the resuscitation of mitochondrial respiration and resynthesis of cellular adenosine triphosphate (ATP).…”

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confidence: 99%

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End‐ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature

Westerkamp

Mahboub²,

Meyer

et al. 2015

Liver Transpl

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A short period of oxygenated machine perfusion (MP) after static cold storage (SCS) may reduce biliary injury in donation after cardiac death (DCD) donor livers. However, the ideal perfusion temperature for protection of the bile ducts is unknown. In this study, the optimal perfusion temperature for protection of the bile ducts was assessed. DCD rat livers were preserved by SCS for 6 hours. Thereafter, 1 hour of oxygenated MP was performed using either hypothermic machine perfusion, subnormothermic machine perfusion, or with controlled oxygenated rewarming (COR) conditions. Subsequently, graft and bile duct viability were assessed during 2 hours of normothermic ex situ reperfusion. In the MP study groups, lower levels of transaminases, lactate dehydrogenase (LDH), and thiobarbituric acid reactive substances were measured compared to SCS. In parallel, mitochondrial oxygen consumption and adenosine triphosphate (ATP) production were significantly higher in the MP groups. Biomarkers of biliary function, including bile production, biliary bicarbonate concentration, and pH, were significantly higher in the MP groups, whereas biomarkers of biliary epithelial injury (biliary gamma-glutamyltransferase [GGT] and LDH), were significantly lower in MP preserved livers. Histological analysis revealed less injury of large bile duct epithelium in the MP groups compared to SCS. In conclusion, compared to SCS, end-ischemic oxygenated MP of DCD livers provides better preservation of biliary epithelial function and morphology, independent of the temperature at which MP is performed. End-ischemic oxygenated MP could reduce biliary injury after DCD liver transplantation. Liver Transpl 21:1300-1311, 2015. V C 2015 AASLD.Received March 17, 2015; accepted June 8, 2015.Ischemic cholangiopathy, also known as nonanastomotic biliary strictures (NAS), is one of the most prevalent and troublesome complications after liver transplantation. During NAS formation, in particular, the large (extrahepatic) bile ducts become fibrotic and/or necrotic. Patients with NAS may suffer from recurrent jaundice and episodes of cholangitis, and retransplantation may be the only curative treatment. 1 The combination of ischemia and ischemia/ reperfusion (I/R) injury has been shown to be a major Additional supporting information may be found in the online version of this article.

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Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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End‐ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature

Westerkamp

Mahboub²,

Meyer

et al. 2015

Liver Transpl

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Mechanism and endoscopic‐treatment‐induced evolution of biliary non‐anastomotic stricture after liver transplantation revealed by single‐cell RNA sequencing

Wu,

Liu,

et al. 2024

Clinical & Translational Med

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BackgroundBiliary complications, especially non‐anastomotic stricture (NAS), are the main complications after liver transplantation. Insufficient sampling and no recognized animal models obstruct the investigation. Thus, the mechanisms and alterations that occur during endoscopic treatment (ET) of NAS remain unclear.MethodsSamples were obtained with endoscopic forceps from the hilar bile ducts of NAS patients receiving continuous biliary stent implantation after diagnosis. Retrospective analysis of multiple studies indicated that the duration of ET for NAS was approximately 1–2 years. Thus, we divided the patients into short‐term treatment (STT) and long‐term treatment (LTT) groups based on durations of less or more than 1 year. Samples were subjected to single‐cell RNA sequencing. Transcriptomic differences between STT and normal groups were defined as the NAS mechanism. Similarly, alterations from STT to LTT groups were regarded as endoscopic‐treatment‐induced evolution.ResultsIn NAS, inflammation and immune‐related pathways were upregulated in different cell types, with nonimmune cells showing hypoxia pathway upregulation and immune cells showing ATP metabolism pathway upregulation, indicating heterogeneity. We confirmed a reduction in bile acid metabolism‐related SPP1+ epithelial cells in NAS. Increases in proinflammatory and profibrotic fibroblast subclusters indicated fibrotic progression in NAS. Furthermore, immune disorders in NAS were exacerbated by an increase in plasma cells and dysfunction of NK and NKT cells. ET downregulated multicellular immune and inflammatory responses and restored epithelial and endothelial cell proportions.ConclusionsThis study reveals the pathophysiological and genetic mechanisms and evolution of NAS induced by ET, thereby providing preventive and therapeutic insights into NAS.Highlights For the first time, single‐cell transcriptome sequencing was performed on the bile ducts of patients with biliary complications. scRNA‐seq analysis revealed distinct changes in the proportion and phenotype of multiple cell types during Nonanastomotic stricture (NAS) and endoscopic treatment. A reduction in bile acid metabolism‐related SPP1+ epithelial cells and VEGFA+ endothelial cells, along with explosive infiltration of plasma cells and dysfunction of T and NK cells in NAS patients. SPP1+ macrophages and BST2+ T cells might serve as a surrogate marker for predicting endoscopic treatment.

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The hepatic, biliary, and pancreatic network of stem/progenitor cell niches in humans: A new reference frame for disease and regeneration

Cardinale²,

2015

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Stem/progenitors for liver, biliary tree, and pancreas exist at early stages of development in the definitive ventral endoderm forming the foregut. In humans, they persist postnatally as part of a network, with evidence supporting their contributions to hepatic and pancreatic organogenesis throughout life. Multiple stem cell niches persist in specific anatomical locations within the human biliary tree and pancreatic ducts. In liver and pancreas, replication of mature parenchymal cells ensures the physiological turnover and the restoration of parenchyma after minor injuries. Although actively debated, multiple observations indicate that stem/progenitor cells contribute to repair pervasive, chronic injuries. The most primitive of the stem/progenitor cells, biliary tree stem cells, are found in peribiliary glands within extrahepatic and large intrahepatic bile ducts. Biliary tree stem cells are comprised of multiple subpopulations with traits suggestive of maturational lineage stages and yet capable of self-replication and multipotent differentiation, being able to differentiate to mature liver cells (hepatocytes, cholangiocytes) and mature pancreatic cells (including functional islet endocrine cells). Hepatic stem cells are located within canals of Hering and bile ductules and are capable of differentiating to hepatocyte and cholangiocyte lineages. The existence, phenotype, and anatomical location of stem/progenitors in the adult pancreas are actively debated. Ongoing studies suggest that pancreatic stem cells reside within the biliary tree, primarily the hepatopancreatic common duct, and are rare in the pancreas proper. Pancreatic ducts and pancreatic duct glands harbor committed pancreatic progenitors. Conclusion: The hepatic, biliary, and pancreatic network of stem/progenitor cell niches should be considered as a framework for understanding liver and pancreatic regeneration after extensive or chronic injuries and for the study of human chronic diseases affecting these organs. (HEPATOLOGY 2016;64:277-286)

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Injury to peribiliary glands and vascular plexus before liver transplantation predicts formation of non-anastomotic biliary strictures

Cited by 165 publications

References 30 publications

End‐ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature

End‐ischemic machine perfusion reduces bile duct injury in donation after circulatory death rat donor livers independent of the machine perfusion temperature

Mechanism and endoscopic‐treatment‐induced evolution of biliary non‐anastomotic stricture after liver transplantation revealed by single‐cell RNA sequencing

The hepatic, biliary, and pancreatic network of stem/progenitor cell niches in humans: A new reference frame for disease and regeneration

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