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Hippo Pathway Activity Influences Liver Cell Fate
Open accessAbstract
The Hippo-signaling pathway is an important regulator of cellular proliferation and organ size. However, little is known about the role of this cascade in the control of cell fate. Employing a combination of lineage tracing, clonal analysis, and organoid culture approaches, we demonstrate that Hippo pathway activity is essential for the maintenance of the differentiated hepatocyte state. Remarkably, acute inactivation of Hippo pathway signaling in vivo is sufficient to dedifferentiate, at very high efficiencies, adult hepatocytes into cells bearing progenitor characteristics. These hepatocyte-derived progenitor cells demonstrate self-renewal and engraftment capacity at the single-cell level. We also identify the NOTCH-signaling pathway as a functional important effector downstream of the Hippo transducer YAP. Our findings uncover a potent role for Hippo/YAP signaling in controlling liver cell fate and reveal an unprecedented level of phenotypic plasticity in mature hepatocytes, which has implications for the understanding and manipulation of liver regeneration.
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“Following diverse injuries, often involving cholestasis, YAP signalling also drives hepatocyte reprogramming via SOX9 induction.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [59]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“These reprogrammed zone 1 hepatocytes exhibited reduced metabolic function, upregulated tissue stem cell markers and increased proliferative capacity, contributing to regeneration.59,60,100,101”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [59]
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In the citing paper
“Acute YAP overexpression results in hepatocyte reprogramming into BEC10.”
From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [10]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“YAP, the main transducer of the Hippo pathway, has been reported to be necessary and sufficient for hepatocyte reprogramming into ductal cells10,11.”
From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [10]
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“Furthermore, increased chromatin accessibility near YAP target genes suggested a pivotal role for YAP/TEAD signaling in the reprogramming process (Figure S1C), supporting previous data10.”
From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [10]
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“Under physiological conditions, activation of YAP is necessary and sufficient to not only reprogram hepatocytes but to precisely control developmental outcomes, organ size and tissue repair10,16,40,41.”
From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [10]
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“Lineage-tracing studies in animal models have confirmed that hepatocytes contribute to bile duct remodeling following cholangiocyte injury10,43–48”
From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [10]
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“In periportal injury, LPLCs are mainly generated in the region 1-5 layers away from injured bile ducts.[7][8][9]12,13”
From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [12]
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“However, YAP promotes SRY-box transcription factor 9 (SOX9) expression in hepatocytes59 and may confer the hybrid hepatocyte-biliary identity of periportal SOX9+ hepatocytes.60”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [59]
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“Hepatocytes display remarkable plasticity and under some conditions can transdifferentiate into BECs, epithelial cells of the bile ducts with completely different morphology, gene expression and function59,[97], [98], [99]”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [59]
The cited source says what the claim attributes to it.
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“Even at this later stage, reprogrammed hepatocytes maintained distinct chromatin accessibility compared to BECs (Figure 1H), despite resembling them morphologically and transcriptionally10 (Figure S1E).”
From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [10]
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In the citing paper
“only very recent studies using a mosaic YAP1 induction model have shown that nuclear YAP1 is able to induce hepatocyte dedifferentiation into clonogenic progenitors in vivo (Yimlamai et al., 2014).”
From Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation (2014) · cites this paper as Yimlamai et al., 2014
In the citing paper
“Further experiments in mice have shown that hepatocytes can change into a biliary ductular phenotype21, 22 then later re-differentiate into hepatocytes23.”
From Hepatic progenitor cells of biliary origin with liver repopulation capacity (2015) · cites this paper as [22]
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Citations
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Metadata
- Authors
- Yimlamai, D., Christodoulou, C., Galli, G. G., Yanger, K., Pepe-Mooney, B., Gurung, B., Shrestha, K., Cahan, P., Stanger, B. Z., & Camargo, F. D.
- Affiliations
- Boston Children's Hospital (US)
- University of Pennsylvania (US)
- Corresponding author
- Camargo, Fernando D.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 157
- Issue
- 6
- Pages
- 1324-1338
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4136468
- OpenAlex
- W2028593002
- Cited by
- 857
- References
- 48
- Citations by year
- 2026: 34 · 2025: 52 · 2024: 62 · 2023: 64 · 2022: 94 · 2021: 82 · 2020: 91 · 2019: 80 · 2018: 79 · 2017: 58 · 2016: 82 · 2015: 57 · 2014: 20
- FWCI
- 36.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AR064036, DK083355, DK099559)
- American-Italian Cancer Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases (5T32 DK007477-27)
- National Science Foundation (DGE1144152)
- U.S. Department of Defense (W81XWH-9)
- Harvard Stem Cell Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- Hippo signaling pathway, YAP, hepatocyte dedifferentiation, hepatic progenitor cells, Notch signaling, phenotypic plasticity, liver regeneration, hepatocyte differentiation
- MeSH terms
- Hippo Signaling Pathway, YAP-Signaling Proteins, Animals, Liver, Phosphoproteins, Stem Cells, Signal Transduction, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Hepatocytes, Adaptor Proteins, Signal Transducing, Mice, Receptors, Notch, Cell Dedifferentiation
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