ArticleCell reports2021
Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors.
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Article in Cell reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 34 citations in OpenAlex.
- Co-repression of Yap1 and Sox9 abrogates established cholangiocarcinoma by eliminating transcriptional compensation.Clinical and molecular hepatology · 2026Article
- Co-repression ofbioRxiv : the preprint server for biology · 2026Article
- Notch signaling in liver diseases: mechanistic insights and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- Nuclear ubiquitination permits Hippo-YAP signal for liver development and tumorigenesis.Nature chemical biology · 2025Article
- Review
- Portal Fibrosis and the Ductular Reaction: Pathophysiological Role in the Progression of Liver Disease and Translational Opportunities.Gastroenterology · 2025Review
- YAP/TAZ as master regulators in liver regeneration and disease: insights into mechanisms and therapeutic targets.Molecular biology reports · 2024Review
- Article
- Interplay between YAP/TAZ and metabolic dysfunction-associated steatotic liver disease progression.Archives of pharmacal research · 2024Review
- PPARα activation promotes liver progenitor cell-mediated liver regeneration by suppressing YAP signaling in zebrafish.Scientific reports · 2023Article
- Nuclear miR-150 enhances hepatic lipid accumulation by targeting RNA transcripts overlapping theiScience · 2023Article
- Physiological and pathological roles of the Hippo-YAP/TAZ signaling pathway in liver formation, homeostasis, and tumorigenesis.Cancer science · 2022Review
- LiverClear: A versatile protocol for mouse liver tissue clearing.STAR protocols · 2022Article
- Role of YAP1 Signaling in Biliary Development, Repair, and Disease.Seminars in liver disease · 2022Review
- Hippo-Yap/Taz signalling in zebrafish regeneration.NPJ Regenerative medicine · 2022Review
- YAP1 activation and Hippo pathway signaling in the pathogenesis and treatment of intrahepatic cholangiocarcinoma.Advances in cancer research · 2022Review
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Authors and funding
25 authors at 2 institutions in 2 countries.
Laura M MolinaMedical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Junjie ZhuDepartment of Pharmaceutical Sciences and Center for Pharmacogenetics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
Qin LiDivision of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA.
Tirthadipa Pradhan-SunddDivision of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA.
Yekaterina KrutsenkoDivision of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Khaled SayedDepartment of Computational and Systems Biology, University of Pittsburgh, 3420 Forbes Ave, Pittsburgh, PA 15213, USA; Biomedical Engineering and Systems, Faculty of Engineering, Cairo University, Giza, Egypt.
Nathaniel JenkinsCenter for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA.
Ravi VatsDivision of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA; Department of Bioengineering, School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA.
Bharat BhushanDivision of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA.
Sungjin KoDivision of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA.
Shikai HuDivision of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Minakshi PoddarDivision of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Sucha SinghDivision of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Junyan TaoDivision of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA.
Prithu SunddDivision of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA.
Aatur SinghiDivision of Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA.
Simon WatkinsCenter for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Xiaochao MaDepartment of Pharmaceutical Sciences and Center for Pharmacogenetics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
Panayiotis V BenosDepartment of Computational and Systems Biology, University of Pittsburgh, 3420 Forbes Ave, Pittsburgh, PA 15213, USA.
Andrew FeranchakDivision of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA.
George MichalopoulosDivision of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA.
Kari Nejak-BowenDivision of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA.
Alan WatsonCenter for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Aaron BellDivision of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA.
Satdarshan P MongaDivision of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA. Electronic address: smonga@pitt.edu.
University of Pittsburgh · USCairo University · EG
Funding
VECTOR CORE FACILITYP30CA047904 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHRISTOPHER J. BAKKENIST · 1988 to 2026
$158.0MPittsburgh Liver Research CenterP30DK120531 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Shuchang Silvia Liu · 2019 to 2026
$10.9MRole of Wnt/Beta-Catenin Signaling in Liver DevelopmentR01DK062277 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Satdarshan Singh Monga · 2004 to 2026
$9.0MCellular Approaches to Tissue Engineering/RegenerationT32EB001026 · NIBIB · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DUNCAN, ANDREW W, MONGA, SATDARSHAN SINGH · 2003 to 2024
$5.5MPulmonary arteriole occlusion by platelet-neutrophil micro-emboli in Acute Chest SyndromeR01HL128297 · NHLBI · VERSITI WISCONSIN, INC. · PI SUNDD, PRITHU · 2015 to 2025
$5.4MMechanisms of platelet exosome-mediated acute chest syndrome in sickle cell diseaseR01HL141080 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI NEAL, MATTHEW D, NOVELLI, ENRICO M · 2019 to 2022
$3.1MDelineating Molecular Mechanisms Underlying Liver Progenitor Cell-Driven Liver RegenerationR01DK116993 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI MONGA, SATDARSHAN SINGH, SHIN, DONGHUN · 2018 to 2021
$2.2MYap and beta-catenin interactions in liver: Implications in PathophysiologyR01CA204586 · NCI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI CHEN, XIN, MONGA, SATDARSHAN SINGH · 2016 to 2020
$2.1MBeta-catenin-driven hepatobiliary reprogramming as a therapeutic modality for cholangiopathiesR01DK119435 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI NEJAK-BOWEN, KARI N · 2019 to 2023
$2.0MRequest for a Nikon A1R Multiphoton MicroscopeS10OD025041 · OD · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI WATKINS, SIMON C · 2018 to 2018
$870kElucidating the Critical Functions of Yap1 in the Embryonic Development and Regeneration of the Biliary SystemF30DK121393 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI MOLINA, LAURA MARIA · 2020 to 2021
$102kNCI NIH HHS P30 CA047904NCI NIH HHS R01 CA204586NHLBI NIH HHS R01 HL128297NHLBI NIH HHS R01 HL141080NIBIB NIH HHS T32 EB001026NIDDK NIH HHS F30 DK121393NIDDK NIH HHS P30 DK120531NIDDK NIH HHS R01 DK062277NIDDK NIH HHS R01 DK116993NIDDK NIH HHS R01 DK119435NIH HHS S10 OD025041
Abstract
Yes-associated protein 1 (YAP1) regulates cell plasticity during liver injury, regeneration, and cancer, but its role in liver development is unknown. We detect YAP1 activity in biliary cells and in cells at the hepatobiliary bifurcation in single-cell RNA sequencing analysis of developing livers. Deletion of Yap1 in hepatoblasts does not impair Notch-driven SOX9+ ductal plate formation but does prevent the formation of the abutting second layer of SOX9+ ductal cells, blocking the formation of a patent intrahepatic biliary tree. Intriguingly, these mice survive for 8 months with severe cholestatic injury and without hepatocyte-to-biliary transdifferentiation. Ductular reaction in the perihilar region suggests extrahepatic biliary proliferation, likely seeking the missing intrahepatic biliary network. Long-term survival of these mice occurs through hepatocyte adaptation via reduced metabolic and synthetic function, including altered bile acid metabolism and transport. Overall, we show YAP1 as a key regulator of bile duct development while highlighting a profound adaptive capability of hepatocytes.
Indexed as
Adaptation, PhysiologicalAnimalsBiliary TractCell TransdifferentiationGenotypeImaging, Three-DimensionalLiverMiceMice, Inbred C57BLMice, KnockoutMorphogenesisRegenerationStem CellsYAP-Signaling ProteinsYap1 protein, mouseYAP-Signaling Proteins3D-tissue clearing and imagingbile acid metabolismbile duct developmentHippo signalingintrahepatic bile ductintravital microscopyliver adaptationliver developmentliver regeneration
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