SOX9 contributes to the progression of ductular reaction for the protection from chronic liver injury

Yoshii, Daiki; Shimata, Keita; Yokouchi, Yuji; Komohara, Yoshihiro; Suda, Hiroko; Honda, Masaki; Yamamura, Ken‐ichi; Hibi, Taizo; Inomata, Yukihiro

doi:10.1007/s13577-022-00683-8

Cited by 6 publications

(3 citation statements)

References 44 publications

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“…In contrast, approximately 10% of patients with BA have a normal gallbladder 55 . A recent study demonstrates the association between intrahepatic SOX9 expression (another SOX factor for cholangiocytes except for the gallbladder walls) and the prognosis in BA 56 . Considering that SOX17-negative (i.e., SOX9+ and/or PDX1+) bile duct progenitors are present in the extrahepatic bile ducts 45 , 46 , 57 , these findings suggest a possible disruption of hepatic and common bile duct walls by the aberrant SOX9+ and/or PDX1+ progenitors in the pathogenesis of other BA groups 10 .…”

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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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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“…Although DR’s link to the progression of liver injury is indisputable, the underlying mechanisms of DR remain unclear in patients with BA. 38 – 43 In preclinical models mimicking BA, blocking Notch signaling decreases cytokeratin-19 expression suggesting that DR arises from hepatic progenitor cells or transdifferentiating hepatocytes instead of self-proliferating cholangiocytes. 8 , 38 , 44 In line with this, PIHs, rather than BE, were increased in follow-up specimens among patients requiring subsequent LT.…”

Section: Discussionmentioning

confidence: 99%

Deep learning quantification reveals a fundamental prognostic role for ductular reaction in biliary atresia

Nyholm,

Sjöblom,

Pihlajoki

et al. 2023

Hepatology Communications

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Background: We aimed to quantify ductular reaction (DR) in biliary atresia using a neural network in relation to underlying pathophysiology and prognosis. Methods: Image-processing neural network model was applied to 259 cytokeratin-7–stained native liver biopsies of patients with biliary atresia and 43 controls. The model quantified total proportional DR (DR%) composed of portal biliary epithelium (BE%) and parenchymal intermediate hepatocytes (PIH%). The results were related to clinical data, Sirius Red–quantified liver fibrosis, serum biomarkers, and bile acids. Results: In total, 2 biliary atresia biopsies were obtained preoperatively, 116 at Kasai portoenterostomy (KPE) and 141 during post-KPE follow-up. DR% (8.3% vs. 5.9%, p=0.045) and PIH% (1.3% vs. 0.6%, p=0.004) were increased at KPE in patients remaining cholestatic postoperatively. After KPE, patients with subsequent liver transplantation or death showed an increase in DR% (7.9%–9.9%, p = 0.04) and PIH% (1.6%–2.4%, p = 0.009), whereas patients with native liver survival (NLS) showed decreasing BE% (5.5%–3.0%, p = 0.03) and persistently low PIH% (0.9% vs. 1.3%, p = 0.11). In Cox regression, high DR predicted inferior NLS both at KPE [DR% (HR = 1.05, p = 0.01), BE% (HR = 1.05, p = 0.03), and PIH% (HR = 1.13, p = 0.005)] and during follow-up [DR% (HR = 1.08, p<0.0001), BE% (HR = 1.58, p = 0.001), and PIH% (HR = 1.04, p = 0.008)]. DR% correlated with Sirius red–quantified liver fibrosis at KPE (R = 0.47, p<0.0001) and follow-up (R = 0.27, p = 0.004). A close association between DR% and serum bile acids was observed at follow-up (R = 0.61, p<0.001). Liver fibrosis was not prognostic for NLS at KPE (HR = 1.00, p = 0.96) or follow-up (HR = 1.01, p = 0.29). Conclusions: DR predicted NLS in different disease stages before transplantation while associating with serum bile acids after KPE.

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“…Gene set enrichment analysis (GSEA) showed that the genetic markers of HPCs are similar to those of YAP transgenic cells and that YAP activation would lead to their proliferative response 35 . Notably, Sox9 is a downstream target of YAP protein activation and contributes to the progression of the ductal response 82 , which may be the initiating source of YAP-promoted HPCs proliferation. Huh-7 cell models co-expressing Sox9 and YAP show a negative feedback pathway between the two and that Sox9 may inhibit YAP transcription and thus interfere with HPCs.…”

Section: Sox9 Hippo/yap and Notch Signalingmentioning

confidence: 99%

Transcriptional Control: A Directional Sign at the Crossroads of Adult Hepatic Progenitor Cells' Fates

Xu,

Fang,

Song

et al. 2024

Int. J. Biol. Sci.

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Hepatic progenitor cells (HPCs) have a bidirectional potential to differentiate into hepatocytes and bile duct epithelial cells and constitute a second barrier to liver regeneration in the adult liver. They are usually located in the Hering duct in the portal vein region where various cells, extracellular matrix, cytokines, and communication signals together constitute the niche of HPCs in homeostasis to maintain cellular plasticity. In various types of liver injury, different cellular signaling streams crosstalk with each other and point to the inducible transcription factor set, including FoxA1/2/3, YB-1, Foxl1, Sox9, HNF4α, HNF1α, and HNF1β. These transcription factors exert different functions by binding to specific target genes, and their products often interact with each other, with diverse cascades of regulation in different molecular events that are essential for homeostatic regulation, self-renewal, proliferation, and selective differentiation of HPCs. Furthermore, the tumor predisposition of adult HPCs is found to be significantly increased under transcriptional factor dysregulation in transcriptional analysis, and the altered initial commitment of the differentiation pathway of HPCs may be one of the sources of intrahepatic tumors. Related transcription factors such as HNF4α and HNF1 are expected to be future targets for tumor treatment.

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SOX9 contributes to the progression of ductular reaction for the protection from chronic liver injury

Cited by 6 publications

References 44 publications

Impact of gallbladder hypoplasia on hilar hepatic ducts in biliary atresia

Impact of gallbladder hypoplasia on hilar hepatic ducts in biliary atresia

Deep learning quantification reveals a fundamental prognostic role for ductular reaction in biliary atresia

Transcriptional Control: A Directional Sign at the Crossroads of Adult Hepatic Progenitor Cells' Fates

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