Prominin‐1‐expressing hepatic progenitor cells induce fibrogenesis in murine cholestatic liver injury

Fenlon, Michael; Short, Celia; Xu, Jiabo; Malkoff, Nicolas; Mahdi, Elaa; Hough, Michelle; Glazier, Alison; Lee, Calvin; Asahina, Kinji; Wang, Kasper S.

doi:10.14814/phy2.14508

Cited by 10 publications

(20 citation statements)

References 40 publications

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“…[16,17] We have shown via cell lineage tracing that Prom1-expressing HPCs contribute to ductular reactions during cholestatic liver injury. [9] Importantly, null mutation of Prom1 and inducible diphtheria toxin ablation of Prom1-expressing HPCs both lead to decreased fibrosis, fibrotic gene markers, ductular reactions, and activated myofibroblasts in murine models of BA. [9,18] In addition, RNA sequencing (RNAseq) analysis of Prom1-expressing HPCs and their progeny revealed upregulation of genes integral to the TGFβ signaling pathway, likely contributing to fibroblast activation and fibrosis.…”

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confidence: 99%

TWEAK/FN14 promotes profibrogenic pathway activation in Prominin-1-expressing hepatic progenitor cells in biliary atresia

Short

Zhong

et al. 2023

Hepatology

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Background and Aims: Biliary atresia (BA), a congenital cholestatic liver disease, commonly culminates in end-stage liver disease. We previously demonstrated in BA that Prominin-1 (Prom1)-expressing hepatic progenitor cells (HPCs) expand within regions of developing fibrosis, giving rise to cholangiocytes within biliary ductular reactions. Null mutation of Prom1 or ablation of cells expressing Prom1 significantly diminishes fibrogenesis. FN14, the receptor for TNF-like weak inducer of apoptosis (TWEAK), is expressed by HPCs. TWEAK/FN14 signaling promotes fibrosis in multiple organ systems. Therefore, we hypothesized that TWEAK/FN14 signaling mediates Prom1-expressing HPC proliferation leading to profibrogenic ductular reactions in BA. Approach and Results: The experimental mouse model of BA mediated by perinatal rhesus rotavirus (RRV) infection resulted in increased co-expression of Fn14 in Prom1-expressing HPCs within regions of ductular reactions. FN14 antagonist L524-0366 decreased ductular reactions, biliary fibrosis and periportal fibroblast activation in RRV injury. L524-0366 inhibition also demonstrated loss of downstream noncanonical NF-kB signaling expression in RRV injury. Murine HPC organoids demonstrated accelerated organoid growth and proliferation when treated with recombinant TWEAK. Increased organoid proliferation with recombinant TWEAK was lost when also treated with L524-0366. Analysis of a large publicly available RNA sequencing database of BA and normal control patients revealed significant increases in

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confidence: 99%

TWEAK/FN14 promotes profibrogenic pathway activation in Prominin-1-expressing hepatic progenitor cells in biliary atresia

Short

Zhong

et al. 2023

Hepatology

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“…CD133 is a stem cell marker and it has been shown that CD133‐positive cancer cells have high levels of TAZ (Cordenonsi et al, 2011; Li et al, 2019). In addition, CD133 is known to be involved in liver fibrosis (Fenlon et al, 2020; Zagory et al, 2019). To study the CD133‐TAZ axis in liver fibrosis after liver damage, CD133‐KO cholangiocyte organoids were prepared from CD133‐KO mice.…”

Section: Resultsmentioning

confidence: 99%

“…The intrahepatic periportal expansion of the CD133 positive cell population was observed in Rhesus rotavirus‐induced BA (Zagory et al, 2019). Further studies revealed that CD133‐expressing hepatic progenitor cells promote biliary fibrosis associated with the activation of myofibroblasts in cholestatic liver injury (Fenlon et al, 2020). However, the mechanism by which CD133 stimulates liver fibrosis remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

CD133‐Src‐TAZ signaling stimulates ductal fibrosis following DDC diet‐induced liver injury

Heo

Yoo

et al. 2022

Journal Cellular Physiology

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Chronic liver injury follows inflammation and liver fibrosis; however, the molecular mechanism underlying fibrosis has not been fully elucidated. In this study, the role of ductal WW domain-containing transcription regulator 1 (WWTR1)/transcriptional coactivator with PDZ-binding motif (TAZ) was investigated after liver injury. Ductal TAZ-knockout (DKO) mice showed decreased liver fibrosis following a Diethyl 1, 4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) diet compared to wild-type (WT) mice, as evidenced by decreased expression levels of fibrosis inducers, including connective tissue growth factor (Ctgf)/cellular communication network factor 2 (CCN2), cysteine-rich angiogenic inducer 61 (Cyr61/CCN1), and transforming growth factor beta 1 (Tgfb1), in DKO mice. Similarly, TAZ-knockout (KO) cholangiocyte organoids showed decreased expression of fibrosis inducers.Additionally, the culture supernatant of TAZ-KO cholangiocyte organoids decreased the fibrogenic gene expression in liver stellate cells. Further studies revealed that prominin 1 (PROM1/CD133) stimulated TAZ for fibrosis. After the administration of DDC diet, fibrosis was decreased in CD133-KO (CD133-KO) mice compared to that in WT mice. Similarly, CD133-KO cholangiocyte organoids showed decreased Ctgf, Cyr61, and Tgfb1 expression levels compared to WT cholangiocyte organoids.Mechanistically, CD133 stabilized TAZ via Src activation. Inhibition of Src decreased TAZ levels. Similarly, CD133-knockdown HCT116 cells showed decreased TAZ levels, but reintroduction of active Src recovered the TAZ levels. Taken together, our results suggest that TAZ facilitates liver fibrosis after a DDC diet via the CD133-Src-TAZ axis.

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“…Liver fibrosis in cholestatic liver diseases, such as BA, may rapidly advance to liver cirrhosis, which often leads to liver failure and requires liver transplantation 25,26 . It is significant to explore the mechanisms and search for effective therapies for cholestatic liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Liver fibrosis in cholestatic liver diseases, such as BA, may rapidly advance to liver cirrhosis, which often leads to liver failure and requires liver transplantation. 25 , 26 It is significant to explore the mechanisms and search for effective therapies for cholestatic liver fibrosis. CDH11, an important adhesion molecule, is implicated in several fibrotic diseases, including dermal fibrosis, pulmonary fibrosis, and CCl 4 ‐induced liver fibrosis, but we don't know if CDH11 has any effect on cholestatic liver fibrosis.…”

Section: Discussionmentioning

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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Prominin‐1‐expressing hepatic progenitor cells induce fibrogenesis in murine cholestatic liver injury

Cited by 10 publications

References 40 publications

TWEAK/FN14 promotes profibrogenic pathway activation in Prominin-1-expressing hepatic progenitor cells in biliary atresia

TWEAK/FN14 promotes profibrogenic pathway activation in Prominin-1-expressing hepatic progenitor cells in biliary atresia

CD133‐Src‐TAZ signaling stimulates ductal fibrosis following DDC diet‐induced liver injury

Upregulation of cadherin‐11 contributes to cholestatic liver fibrosis

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