SOX9 in biliary atresia: New insight for fibrosis progression

El-Araby, Hanaa Ahmed; Saber, Magdy Anwar; Radwan, Noha M; Taie, Doha Maher; Adawy, Nermin Mohammed; Sira, Ahmad Mohamed

doi:10.1016/j.hbpd.2020.12.007

Cited by 13 publications

(12 citation statements)

References 34 publications

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“…There have been sporadic reports that the transcription factor SOX9 is associated with the prognostic factors of BA [ 40 , 41 ]; however, the identity of these SOX9-positive cells was unclear. As we have mentioned earlier, SOX9 as one of the HPC markers has a certain degree of overlap with cholangiocyte markers.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of SOX9-positive progenitor-like cells during cholestatic liver regeneration in biliary atresia

Lin

Zhang

et al. 2022

Stem Cell Res Ther

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Background The progression of Biliary Atresia (BA) is associated with the number of reactive ductular cells (RDCs) whose heterogeneity in origin and evolution in humans remains unknown. SOX9-positive liver progenitor-like cells (LPLCs) have been shown to participate in RDCs and new hepatocyte formation during cholestatic liver regeneration in an animal model, which implies the possibility that hepatocyte-reprogrammed LPLCs could be a source of RDCs in BA. The present study aimed to elucidate the characteristics of SOX9-positive LPLCs in BA for exploring new possible therapeutic targets by manipulating the bi-differentiation process of LPLCs to prevent disease progression. Methods Twenty-eight patients, including 24 patients with BA and 4 patients with Congenital Choledochal Cyst as the control group, were retrospectively recruited. Liver biopsy samples were classified histologically using a 4-point scale based on fibrosis severity. LPLCs were detected by SOX9 and HNF4A double positive staining. Single immunohistochemistry, double immunohistochemistry, and multiple immunofluorescence staining were used to determine the different cell types and characteristics of LPLCs. Results The prognostic predictors of BA, namely total bile acid (TBA), RDCs, and fibrosis, were correlated to the emergence of LPLCs. SOX9 and HNF4A double-positive LPLCs co-stained rarely with relevant markers of portal hepatic progenitor cells (portal-HPCs), including CK19, CK7, EPCAM, PROM1 (CD133), TROP2, and AFP. Under cholestasis conditions, LPLCs acquired superior proliferation and anti-senescence ability among hepatocytes. Moreover, LPLCs arranged as a pseudo-rosette structure appeared from the periportal parenchyma to the portal region, which implied the differentiation from hepatocyte-reprogrammed LPLCs to RDCs with the progression of cholestasis. Conclusions LPLCs are associated with disease progression and prognostic factors of BA. The bipotent characteristics of LPLCs are different from those of portal-HPCs. As cholestasis progresses, LPLCs appear to gain superior proliferation and anti-senescence ability and continually differentiate to RDCs.

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Section: Discussionmentioning

confidence: 99%

Characteristics of SOX9-positive progenitor-like cells during cholestatic liver regeneration in biliary atresia

Lin

Zhang

et al. 2022

Stem Cell Res Ther

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“…Excessive accumulation of bile components, including bile acid, cholesterol and bilirubin, in hepatic and systemic circulation is considered the major driver of liver injury. Currently, adults with different phenotypes of cholestasis have increasingly been evaluated for variants in these genes to identify specific cholestasis-related genes [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Human menstrual blood-derived stem cell transplantation suppresses liver injury in DDC-induced chronic cholestasis

et al. 2022

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Background Cholestatic liver injury can lead to serious symptoms and prognoses in the clinic. Currently, an effective medical treatment is not available for cholestatic liver injury. Human menstrual blood-derived stem cells (MenSCs) are considered as an emerging treatment in various diseases. This study aimed to explore the treatment effect of MenSCs in cholestatic liver injury. Methods The treatment effect of MenSCs on chronic cholestatic liver injury was verified in 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC)-induced C57/BL6 mice. Pathological, fibrosis area in the liver tissue and serum liver enzymes were tested. Proteomics and western blot were used to explore the related targets and molecular mechanisms. Adeno-associated virus (AAV) 9-infected mice were applied for verification. Results MenSCs markedly improved the survival rate of the DDC-treated mice (60% vs. 100%), and decreased the mouse serum aspartate aminotransferase (AST) (169.4 vs. 108.0 U/L, p < 0.001), alanine aminotransferase (ALT) (279.0 vs. 228.9 U/L, p < 0.01), alkaline phosphatase (ALP) (45.6 vs. 10.6 U/L, p < 0.0001), direct bilirubin (DBIL) (108.3 vs. 14.0 μmol/L, p < 0.0001) and total bilirubin (TBIL) (179.2 vs. 43.3 μmol/L, p < 0.0001) levels as well as intrahepatic cholestasis, bile duct dilation and fibrotic areas (16.12 vs. 6.57%, p < 0.05). The results further indicated that MenSCs repaired the DDC-induced liver tight junction (TJ) pathway and bile transporter (OATP2, BSEP and NTCP1) injury, thereby inhibiting COL1A1, α-SMA and TGF-β1 activation by upregulating liver β-catenin expression. Conclusions MenSC transplantation could be an effective treatment method for cholestatic liver injury in mice. MenSCs may exhibit therapeutic effects by regulating β-catenin expression.

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“…Although the Kasai portoenterostomy has improved the prognosis of BA, BA is still the major cause of liver transplantation in children 16,17 . Liver fibrosis is a pathological scarring process of liver damage 14 . The process of liver fibrosis is initiated when the growth factors, especially transforming growth factor‐β (TGF‐β), are synthesized and secreted under the stimulation of liver injury 18 .…”

Section: Introductionmentioning

confidence: 99%

“… 12 , 13 In BA, cholestatic liver fibrosis may progress rapidly to liver cirrhosis and endanger children's life. 14 Kasai portoenterostomy is regarded as a first‐line treatment choice for BA and it can rebuild bile flow from the liver to the intestine. 15 Although the Kasai portoenterostomy has improved the prognosis of BA, BA is still the major cause of liver transplantation in children.…”

Section: Introductionmentioning

confidence: 99%

Upregulation of cadherin‐11 contributes to cholestatic liver fibrosis

Tian

Wang

et al. 2022

Pediatric Investigation

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Importance: , a cell-to-cell adhesion molecule, is implicated in the fibrotic process of several organs. Biliary atresia (BA) is a common cholestatic liver disease featuring cholestasis and progressive liver fibrosis in children. Cholestatic liver fibrosis may progress to liver cirrhosis and lacks effective therapeutic strategies. Currently, the role of CDH11 in cholestatic liver fibrosis remains unclear.Objective: This study aimed to explore the functions of CDH11 in cholestatic liver fibrosis. Methods: The expression of CDH11 in BA livers was evaluated by database analysis and immunostaining. Seven BA liver samples were used for immunostaining. The wild type (Wt) and CDH11 knockout (CDH11 -/-) mice were subjected to bile duct ligation (BDL) to induce cholestatic liver fibrosis. The serum biochemical analysis, liver histology, and western blotting were used to assess the extent of liver injury and fibrosis as well as activation of transforming growth factor-β (TGF-β)/Smad pathway. The effect of CDH11 on the activation of hepatic stellate cell line LX-2 cells was investigated. Results: Analysis of public RNA-seq datasets showed that CDH11 expression levels were significantly increased in livers of BA, and CDH11 was correlated with liver fibrosis in BA. BDL-induced liver injury and liver fibrosis were attenuated in CDH11 -/mice compared to Wt mice. The protein expression levels of phosphorylated Smad2/3 were decreased in livers of CDH11 -/-BDL mice compared to Wt BDL mice. CDH11 knockdown inhibited the activation of LX-2 cells. Interpretation: CDH11 plays an important role in cholestatic liver fibrosis and may represent a potential therapeutic target for cholestatic liver disease, such as BA.

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SOX9 in biliary atresia: New insight for fibrosis progression

Cited by 13 publications

References 34 publications

Characteristics of SOX9-positive progenitor-like cells during cholestatic liver regeneration in biliary atresia

Characteristics of SOX9-positive progenitor-like cells during cholestatic liver regeneration in biliary atresia

Human menstrual blood-derived stem cell transplantation suppresses liver injury in DDC-induced chronic cholestasis

Upregulation of cadherin‐11 contributes to cholestatic liver fibrosis

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