YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury
Open accessAbstract
Biliary epithelial cells (BECs) form bile ducts in the liver and are facultative liver stem cells that establish a ductular reaction (DR) to support liver regeneration following injury. Liver damage induces periportal LGR5+ putative liver stem cells that can form BEC-like organoids, suggesting that RSPO-LGR4/5-mediated WNT/β-catenin activity is important for a DR. We addressed the roles of this and other signaling pathways in a DR by performing a focused CRISPR-based loss-of-function screen in BEC-like organoids, followed by in vivo validation and single-cell RNA sequencing. We found that BECs lack and do not require LGR4/5-mediated WNT/β-catenin signaling during a DR, whereas YAP and mTORC1 signaling are required for this process. Upregulation of AXIN2 and LGR5 is required in hepatocytes to enable their regenerative capacity in response to injury. Together, these data highlight heterogeneity within the BEC pool, delineate signaling pathways involved in a DR, and clarify the identity and roles of injury-induced periportal LGR5+ cells.
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Cholestatic injury activates YAP signalling and thereby reprogrammes periportal hepatocytes, reducing the amount of metabolically active workers in this zone.
“Such cholestatic injury also activates YAP signalling and thereby reprogrammes periportal hepatocytes, reducing the amount of metabolically active workers in this zone.57,94,102”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [57]
The Results report YAP activation in periportal hepatocytes after DDC-induced injury and a YAP-dependent increase in SOX9-positive periportal hepatocytes (page not provided). This supports a change in hepatocyte state, but the cited passages do not show that it reduces the number of metabolically active hepatocytes in that zone. (LLM, conf=0.85)
Experimental — accuracy not yet measuredYAP activation in liver regeneration reprograms a subset of periportal hepatocytes into SOX9+ progenitor-like cells that can give rise to both cholangiocytes and hepatocytes.
“YAP activation in liver regeneration has been shown to reprogram a subset of periportal hepatocytes into SOX9+ progenitor-like cells (PLCs) that can give rise to both cholangiocytes and hepatocytes (51, 52).”
From Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 (2022) · cites this paper as [52]
The Results (page unavailable) report YAP signaling in periportal hepatocytes after liver injury and an increase in SOX9+ periportal hepatocytes in controls but not YAP-deleted mice. The Discussion (page unavailable) describes a hybrid biliary epithelial cell–hepatocyte signature but treats its origin as uncertain. The paper does not establish that the YAP-associated SOX9+ hepatocytes are progenitor-like cells capable of giving rise to both cholangiocytes and hepatocytes. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn response to cholestatic injury, BECs upregulate WNT ligands.
“In response to cholestatic injury, BECs upregulate WNT ligands.57,94,109,110”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [57]
CRISPR cutting screens in 3D organoids have been implemented to explore factors such as growth factor dependency for cell growth, identify potential cancer-driving forces, and uncover key genetic events in cell differentiation.
“Even more exciting is the implementation of CRISPR cutting screens in 3D organoids to explore factors such as growth factor dependency for cell growth14–16, identifying potential cancer-driving forces17–19, and uncovering key genetic events in cell differentiation20–22.”
From Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions (2025) · cites this paper as [16]
Activated YAP signalling reversibly increased liver size, but its deletion did not affect liver size during homeostasis.
“While activated YAP signalling reversibly increased liver size,93 its deletion did not affect liver size during homeostasis.57,58,94”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [57]
Citation 94 is attached to the claim that YAP deletion did not affect liver size during homeostasis. The Results describe naive YapDEL mice as having comparable bilirubin levels to controls and no significant hepatocyte damage, but do not report liver size in those mice. Searches for liver size, liver weight, and liver-to-body-weight ratio did not locate a measurement that settles the claim. (LLM, conf=0.72)
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Self-citationTargeting acid ceramidase inhibits YAP/TAZ signaling to reduce fibrosis in mice
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Self-citationWnt-β-catenin in hepatobiliary homeostasis, injury, and repair
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- Authors
- Planas-Paz, L., Sun, T., Pikiolek, M., Cochran, N. R., Bergling, S., Orsini, V., Yang, Z., Sigoillot, F., Jetzer, J., Syed, M., Neri, M., Schuierer, S., Morelli, L., Hoppe, P. S., Schwarzer, W., Cobos, C. M., Alford, J. L., Zhang, L., Cuttat, R., Waldt, A., Carballido-Perrig, N., Nigsch, F., Kinzel, B., Nicholson, T. B., Yang, Y., Mao, X., Terracciano, L. M., Russ, C., Reece-Hoyes, J. S., Gubser Keller, C., Sailer, A. W., Bouwmeester, T., Greenbaum, L. E., Lugus, J. J., Cong, F., McAllister, G., Hoffman, G. R., Roma, G., & Tchorz, J. S.
- Affiliations
- Novartis (Switzerland) (CH)
- University Hospital of Basel (CH)
- Corresponding author
- Tchorz, Jan S.
- ORCID
- Sun, Tianliang
- Bergling, Sebastian
- Yang, Zinger
- Sigoillot, Frederic
- Jetzer, Jasna
- Neri, Marilisa
- Schuierer, Sven
- Hoppe, Philipp S.
- Schwarzer, Wibke
- Cuttat, Rachel
- Waldt, Annick
- Nigsch, Florian
- Nicholson, Thomas B.
- Yang, Yi
- Terracciano, Luigi M.
- Reece-Hoyes, John S.
- Sailer, Andreas W.
- Bouwmeester, Tewis
- Cong, Feng
- Roma, Guglielmo
- Tchorz, Jan S.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 25
- Issue
- 1
- Pages
- 39-53.e10
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2944293957
- Cited by
- 216
- References
- 90
- Citations by year
- 2026: 16 · 2025: 19 · 2024: 24 · 2023: 29 · 2022: 47 · 2021: 35 · 2020: 32 · 2019: 14
- FWCI
- 20.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- The Novartis Repository (Novartis) (acceptedVersion)
- Funders
- Novartis
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- cholangiocytes, ductular reaction, liver injury, liver regeneration, YAP signaling, mTORC1 signaling, Wnt/β-catenin signaling, RSPO, Axin2, Lgr5
- MeSH terms
- YAP-Signaling Proteins, Animals, Bile Ducts, Cells, Cultured, Disease Models, Animal, Epithelial Cells, Humans, Liver Regeneration, Male, Mice, Inbred C57BL, Pyridines, Cell Cycle Proteins, Thrombospondins, Receptors, G-Protein-Coupled, Adaptor Proteins, Signal Transducing, Mice, Acute Lung Injury, Induced Pluripotent Stem Cells, Wnt Signaling Pathway, Axin Protein, Clustered Regularly Interspaced Short Palindromic Repeats
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