Rhesus rotavirus receptor‐binding site affects high mobility group box 1 release, altering the pathogenesis of experimental biliary atresia

Mohanty, Sujit K.; Donnelly, Bryan; Temple, Haley; Mowery, Sarah; Poling, Holly M.; Meller, Jarosław; Malik, Astha; McNeal, Monica; Tiao, Greg

doi:10.1002/hep4.2024

Cited by 5 publications

(5 citation statements)

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“…In our deconvoluted gene network of HMGB1, its predicted targets were in the vast majority enriched in pathways related to cellular response to epidermal growth factor stimulus, positive regulation of transforming growth factor beta1, immune system development (Supplementary Table S11). The signal pathways descripted above have been proven to be altered in BA (44)(45)(46). Some TFs, such as FOXA2, SOX17 have been reported to be the risk factors for BA.…”

Section: Discussionmentioning

confidence: 95%

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A joint transcriptional regulatory network and protein activity inference analysis identifies clinically associated master regulators for biliary atresia

et al. 2022

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Biliary atresia (BA) is a devastating cholangiopathy in neonate. Transcription factors (TFs), a type of master regulators in biological processes and diseases, have been implicated in pathogenesis of BA. However, a global view of TFs and how they link to clinical presentations remain explored. Here, we perform a joint transcriptional regulatory network and protein activity inference analysis in order to investigate transcription factor activity in BA. By integration of three independent human BA liver transcriptome datasets, we identify 22 common master regulators, with 14 activated- and 8 repressed TFs. Gene targets of activated TFs are enriched in biological processes of SMAD, NF-kappaB and TGF-beta, while those of repressed TFs are related to lipid metabolism. Mining the clinical association of TFs, we identify inflammation-, fibrosis- and survival associated TFs. In particular, ZNF14 is predictive of poor survival and advanced live fibrosis. Supporting this observation, ZNF14 is positively correlated with T helper cells, cholangiocytes and hepatic stellate cells. In sum, our analysis reveals key clinically associated master regulators for BA.

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Section: Discussionmentioning

confidence: 95%

“…These pathways are closely associated with BA. HMGB1 has been reported to be associated with pathogenesis of BA (44)(45)(46). BP pathways for activated HMGB1 gene are related to negative regulation of transcription by RNA polymerase II, inflammatory response to antigenic stimulus and immune system process (Supplementary Table S10).…”

Section: Discussionmentioning

confidence: 99%

A joint transcriptional regulatory network and protein activity inference analysis identifies clinically associated master regulators for biliary atresia

et al. 2022

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“…It is speculated that BAs are initiated by various factors such as virus infection 47 , toxins 48 and genetic defects 8 , suggesting the presence of the various subtypes even in the isolated BAs. A recent genome-wide association study (GWAS) of 811 human BA genome samples also supports the involvement of the multiple genes including SOX17 , to contribute to the onset and/or exacerbation of BA 49 .…”

Section: Discussionmentioning

confidence: 99%

Impact of gallbladder hypoplasia on hilar hepatic ducts in biliary atresia

Miyazaki,

Takami,

Uemura

et al. 2024

Commun Med

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Background Biliary atresia (BA) is an intractable disease of unknown cause that develops in the neonatal period. It causes jaundice and liver damage due to the destruction of extrahepatic biliary tracts,. We have found that heterozygous knockout mice of the SRY related HMG-box 17 (Sox17) gene, a master regulator of stem/progenitor cells in the gallbladder wall, exhibit a condition like BA. However, the precise contribution of hypoplastic gallbladder wall to the pathogenesis of hepatobiliary disease in Sox17 heterozygous embryos and human BA remains unclear. Methods We employed cholangiography and histological analyses in the mouse BA model. Furthermore, we conducted a retrospective analysis of human BA. Results We show that gallbladder wall hypoplasia causes abnormal multiple connections between the hilar hepatic bile ducts and the gallbladder-cystic duct in Sox17 heterozygous embryos. These multiple hilar extrahepatic ducts fuse with the developing intrahepatic duct walls and pull them out of the liver parenchyma, resulting in abnormal intrahepatic duct network and severe cholestasis. In human BA with gallbladder wall hypoplasia (i.e., abnormally reduced expression of SOX17), we also identify a strong association between reduced gallbladder width (a morphometric parameter indicating gallbladder wall hypoplasia) and severe liver injury at the time of the Kasai surgery, like the Sox17-mutant mouse model. Conclusions Together with the close correlation between gallbladder wall hypoplasia and liver damage in both mouse and human cases, these findings provide an insight into the critical role of SOX17-positive gallbladder walls in establishing functional bile duct networks in the hepatic hilus of neonates.

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“…Matrix stiffness has previously been shown to alter glutathione metabolism. 101,102 Cells cultured using softer matrices were shown to be more resistant to oxidative stress by replenishing the redox balance rapidly. Meanwhile, cells cultured using stiffer matrices were less responsive to oxidative stress.…”

Section: Biliatresonementioning

confidence: 99%

“…100,101 Certain amino acid sequences have been identified to bind to cell surface receptors. 101,102 Specifically, the amino acid sequence SRL present on capsid or attachment proteins of various viruses associated with BA has been identified as a key player. 101,[103][104][105] This peptide specifically binds to the cell surface domain of the cholangiocyte heat shock cognate 70 (Hsc70).…”

Section: Liver Organoids To Study Biliary Atresiamentioning

confidence: 99%

The Modern Day Heracles

Lehmann

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Rare pediatric liver disorders can be very destructive to the lives of patients and their families. Often, therapeutic options are limited to symptomatic care and precise disease mechanisms remain elusive. The relatively low incidence of each individual disease and the often widespread geographic distribution of patients complicate research and treatment development. In this thesis, we have investigated the potential of patient-derived liver organoids to study such rare pediatric liver diseases. We characterized intrahepatic cholangiocyte organoids (ICOs) from several monogenic liver disorders and showed that organoids express affected proteins of diseases such as cystic fibrosis, Wilson disease and methylmalonic acidemia. We uncovered that ICOs possess a hybrid phenotype, combining hepatocyte and cholangiocyte characteristics. This led us to investigate whether patient-derived liver organoids would be interesting to study the rare perinatal disease biliary atresia (BA), in which the hepatobiliary tree is occluded and becomes fibrotic. We found that organoids from different hepatobiliary regions (intrahepatic, extrahepatic and gallbladder) of BA patients can be cultured and biobanked. Further characterization showed that BA patient organoids display BA specific growth behavior and increased sensitivity to viral infections. While we showed that various hepatocyte and cholangiocyte functions can be studied in liver organoids, our data also indicated that several hepatocyte functions are currently limited in this in vitro system. Therefore, we devised a novel culture strategy to increase hepatic maturation in liver organoids. We found that hepatic functions, such as drug metabolism, improve when liver organoid cells are cultured on hollow fiber membranes coated with extracellular matrix proteins of the hepatic niche. Moreover, we demonstrated that hepatic transepithelial transporter defects such as progressive familial intrahepatic cholestasis type 3 can be studied in patient-derived liver organoids. In summary, we have demonstrated that patient-derived liver organoids are a useful tool to study various rare liver and metabolic disorders affecting the hepatobiliary tract. Several diseases such as BA, cystic fibrosis, Wilson disease, progressive familial intrahepatic cholestasis type 3 and methylmalonic acidemia can currently be studied with ICOs. Although ICOs were previously praised as a new break-through hepatocyte model, we have shown that organoids from all hepatobiliary regions are at least equally useful for researching cholangiopathies, such as BA. The development of new technologies, such as organ chips and co-culture strategies, are exciting not only to study the disease mechanisms of rare diseases but also to improve the hepatic maturity of ICOs. Applying the myriad of culture improvement strategies to ICOs will likely produce a fantastic patient-derived hepatocyte model. We have taken the first steps toward improving hepatic maturation of ICOs and in doing so have demonstrated that the ICO application range can be broadened to facilitate the study of (cholestatic) disease mechanisms. Similarly, we anticipate that these improvements in hepatic maturation of ICOs will aid in the development of safe therapeutics for (rare) liver diseases in a personalized manner in the future.

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Rhesus rotavirus receptor‐binding site affects high mobility group box 1 release, altering the pathogenesis of experimental biliary atresia

Cited by 5 publications

References 50 publications

A joint transcriptional regulatory network and protein activity inference analysis identifies clinically associated master regulators for biliary atresia

A joint transcriptional regulatory network and protein activity inference analysis identifies clinically associated master regulators for biliary atresia

Impact of gallbladder hypoplasia on hilar hepatic ducts in biliary atresia

The Modern Day Heracles

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