YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury

Planas-Paz, Lara; Sun, Tianliang; Pikiolek, Monika; Cochran, Nadire; Bergling, Sebastian; Orsini, Vanessa; Yang, Zinger; Sigoillot, Frederic; Jetzer, Jasna; Syed, Maryam; Neri, Marilisa; Schuierer, Sven; Morelli, Lapo; Hoppe, Philipp S.; Schwarzer, Wibke; Cobos, C.; Alford, John; Zhang, Le; Cuttat, Rachel; Waldt, Annick; Carballido‐Perrig, Nicole; Nigsch, Florian; Kinzel, Bernd; Nicholson, Thomas B.; Yang, Yi; Mao, Xiaohong; Terracciano, Luigi; Russ, Carsten; Reece‐Hoyes, John S.; Keller, Caroline Gubser; Sailer, Andreas W.; Bouwmeester, Tewis; Greenbaum, Linda E.; Lugus, Jesse J.; Cong, Feng; McAllister, Gregory; Hoffman, Gregory R.; Roma, Guglielmo; Tchorz, Jan S.

doi:10.1016/j.stem.2019.04.005

Cited by 168 publications

(224 citation statements)

References 92 publications

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“…In a separate CRISPR-based screen for regulators of ductular reaction using BEC-like organoids, Planas-Paz et al also uncovered YAP as a factor that serves a critical role in triggering ductular reaction following DDC-induced liver injury. (20) In contrast, Wnt/β catenin signaling appeared to be dispensable for injury-induced BEC expansion and ductular reaction. Single-cell transcriptomic analysis revealed a molecular signature that is consistent with robust YAP signaling in EpCAM+ ECs.…”

Section: Single-cell Perspective Of Liver Development and Regenerationmentioning

confidence: 97%

“…Interestingly, hepatocyte‐specific YAP inactivation revealed a crucial role for this signaling pathway in injury‐induced reprogramming of hepatocytes toward a progenitor, biliary‐like cell fate. In a separate CRISPR‐based screen for regulators of ductular reaction using BEC‐like organoids, Planas‐Paz et al also uncovered YAP as a factor that serves a critical role in triggering ductular reaction following DDC‐induced liver injury . In contrast, Wnt/β catenin signaling appeared to be dispensable for injury‐induced BEC expansion and ductular reaction.…”

Section: Single‐cell Perspective Of Liver Development and Regenerationmentioning

confidence: 99%

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A Single‐Cell Perspective of the Mammalian Liver in Health and Disease

et al. 2020

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Section: Single-cell Perspective Of Liver Development and Regenerationmentioning

confidence: 97%

Section: Single‐cell Perspective Of Liver Development and Regenerationmentioning

confidence: 99%

A Single‐Cell Perspective of the Mammalian Liver in Health and Disease

et al. 2020

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“…Morphogenic signals such as Wnt/β-catenin, Hedgehog, Notch, TNF-related weak inducer of apoptosis (TWEAK)/ fibroblast growth factor-inducible 14 (Fn14), and, more recently, Yes-associated protein/Hippo pathways have all been implicated in DRC activation and expansion. (18,19) In particular, macrophage-derived TWEAK induces progenitor cell expansion and biliary duct hyperplasia in healthy mice, and progenitor cell expansion in mouse models of cholestasis is prevented in Fn14-deficient mice or by neutralization of TWEAK. (20,21) Increased Fn14 expression is seen in DRCs from human chronic liver diseases associated with intense ductular reaction, including PSC.…”

Section: The Proliferative Cholangiocyte Compartment In Psc: Drcsmentioning

confidence: 99%

The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis

et al. 2020

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Cholangiocytes are the target of a group of chronic liver diseases termed the “cholangiopathies,” in which cholangiocytes react to exogenous and endogenous insults, leading to disease initiation and progression. In primary sclerosing cholangitis (PSC), the focus of this review, the cholangiocyte response to genetic or environmental insults can lead to a heterogeneous response; that is, a subpopulation acquires a ductular reactive and proliferative phenotype, while another subpopulation undergoes senescence and growth arrest. Both ductular reactive cholangiocytes and senescent cholangiocytes can modify the periductal microenvironment through their ability to secrete various cytokines, chemokines, and growth factors, initiating and perpetuating inflammatory and profibrotic responses. This review discusses the similarities and differences, the interrelationships, and the potential pathogenic roles of these reactive proliferative and senescent cholangiocyte subpopulations in PSC.

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“…Interestingly, BDL-treated Prom1 -/- mice exhibited more CK19-expressing cells than to Prom1 +/+ mice, suggesting that PROM1 is not necessary for the proliferation of CK19-expressing cells during liver fibrosis. Recent reports also show that PROM1 does not affect cholangiocyte proliferation in cholangiocyte-derived liver organoid 25, 26 . Thus, PROM1 upregulation in the fibrotic liver of human patients and mice is the simple consequence of cholangiocyte proliferation.…”

Section: Discussionmentioning

confidence: 92%

Hepatocytic Prominin-1 protects against liver fibrosis by stabilizing the SMAD7 protein

Lee¹,

Dong²,

Um³

et al. 2019

Preprint

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Background and Aims:Prominin-1 (PROM1) is known to be upregulated in hepatocytic progenitor cells (HPCs) and cholangiocytes of fibrotic livers. To understand the function of upregulated PROM1 during liver fibrosis, we analyzed liver fibrosis from global and liverspecific Prom1 knockout mice and investigated the molecular mechanism of how Prom1 protects the liver against liver fibrosis. Methods:We analyzed PROM1 expression from human liver with mild and severe liver fibrosis (n=4-9). Liver fibrosis was induced by carbon tetrachloride (CCl 4 ) treatment and bile duct ligation (BDL) from wild type and global and liver-specific knockout mice (n=3-13).The severity of liver fibrosis was determined by qRT-PCR, immunostaining and immunoblotting for fibrotic markers such as αSMA, collagen. TGFβ signaling was also analyzed from fibrotic liver and primary hepatocytes of wild type and global and liverspecific knockout mice (n=3-5). Molecular interaction between PROM1 and SMAD7 was determined by endogenous and exogenous co-immunoprecipitation.Results: PROM1 was found in the plasma membranes of both healthy and fibrotic hepatocytes and cholangiocytes. Global Prom1 knockout aggravated BDL-and CCl 4 -induced liver fibrosis. Prom1 -/hepatocytes showed increased TGFβ signaling due to reduced SMAD7 protein expression compared to that in wild-type hepatocytes. PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated that liver-specific Prom 1 knockout aggravated BDL-induced liver fibrosis due to reduced levels of SMAD7. Conclusion:Hepatocytic PROM1 stabilizes SMAD7, preventing TGFβ signaling. Thus, PROM1 is necessary for the negative regulation of TGFβ signaling during liver fibrosis.

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YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury

Cited by 168 publications

References 92 publications

A Single‐Cell Perspective of the Mammalian Liver in Health and Disease

A Single‐Cell Perspective of the Mammalian Liver in Health and Disease

The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis

Hepatocytic Prominin-1 protects against liver fibrosis by stabilizing the SMAD7 protein

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