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Cited by 148Liver physiology and pathologyHippo pathway signaling and YAP/TAZTGF-β signaling in diseases

Liver regeneration requires Yap1-TGFβ-dependent epithelial-mesenchymal transition in hepatocytes

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Oh, Seh-Hoon, Swiderska-Syn, Marzena, Jewell, Mark L., Premont, Richard T., Diehl, Anna Mae·2018·Journal of Hepatology
DOI 10.1016/j.jhep.2018.05.008PMC PMC6349217
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Abstract

Background & Aims Chronic failure of mechanisms that promote effective regeneration of dead hepatocytes causes replacement of functional hepatic parenchyma with fibrous scar tissue, ultimately resulting in cirrhosis. Therefore, defining and optimizing mechanisms that orchestrate effective regeneration might prevent cirrhosis. We hypothesized that effective regeneration of injured livers requires hepatocytes to evade the growth-inhibitory actions of TGFβ, since TGFβ signaling inhibits mature hepatocyte growth but drives cirrhosis pathogenesis. Methods Wild-type mice underwent 70% partial hepatectomy (PH); TGFβ expression and signaling were evaluated in intact tissue and primary hepatocytes before, during, and after the period of maximal hepatocyte proliferation that occurs from 24–72 h after PH. To determine the role of Yap1 in regulating TGFβ signaling in hepatocytes, studies were repeated after selectively deleting Yap1 from hepatocytes of Yap1 flox/flox mice. Results TGFβ expression and hepatocyte nuclear accumulation of pSmad2 and Yap1 increased in parallel with hepatocyte proliferative activity after PH. Proliferative hepatocytes also upregulated Snai1 , a pSmad2 target gene that promotes epithelial-to-mesenchymal transition (EMT), suppressed epithelial genes, induced myofibroblast markers, and produced collagen 1α1. Deleting Yap1 from hepatocytes blocked their nuclear accumulation of pSmad2 and EMT-like response, as well as their proliferation. Conclusion Interactions between the TGFβ and Hippo-Yap signaling pathways stimulate hepatocytes to undergo an EMT-like response that is necessary for them to grow in a TGFβ-enriched microenvironment and regenerate injured livers. Lay summary The adult liver has an extraordinary ability to regenerate after injury despite the accumulation of scar-forming factors that normally block the proliferation and reduce the survival of residual liver cells. We discovered that liver cells manage to escape these growth-inhibitory influences by transiently becoming more like fibroblasts themselves. They do this by reactivating programs that are known to drive tissue growth during fetal development and in many cancers. Understanding how the liver can control programs that are involved in scarring and cancer may help in the development of new treatments for cirrhosis and liver cancer.

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  • Mice with liver-specific deletion of Yap or Yap and Taz suffer significantly blunted liver weight restoration after PHx.

    “Mice with liver-specific deletion of Yap or Yap and Taz suffer significantly blunted liver weight restoration after PHx (55, 56).”

    From Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 (2022) · cites this paper as [55]

    The Results section reports that hepatocyte-specific Yap1 deletion reduced hepatocyte proliferation by about 50% at 48 hours after partial hepatectomy. It does not report significantly blunted liver-weight restoration, and the Animal Experiments section describes no combined Yap1/Taz deletion. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Liver-specific deletion of Yap or Yap and Taz significantly blunts liver weight restoration after PHx, similar to IL-6-knockout mice.

    “Mice with liver-specific deletion of Yap or Yap and Taz suffer significantly blunted liver weight restoration after PHx (55, 56), similar to IL-6–knockout mice (39).”

    From Senescent hepatic stellate cells promote liver regeneration through IL-6 and ligands of CXCR2 (2022) · cites this paper as [55]

    The Results section reports that hepatocyte-specific Yap1 deletion reduced hepatocyte proliferation by about 50% at 48 hours after partial hepatectomy. It does not report liver-weight restoration or test combined Yap1/Taz deletion. The IL-6-knockout comparison has a separate citation in the citing sentence and is not attributed to this paper. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Hepatocytes underwent an EMT-like response to enable them to grow in a TGFβ-enriched microenvironment.

    “Hepatocytes also underwent an EMT (epithelial-mesenchymal transition)-like response to enable them to grow in a TGFβ-enriched microenvironment.108”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [108]

  • A recent update to the theory is that hepatocytes transiently undergo reprogramming (EMT, or fetal gene expression) as they proliferate.

    “A recent update to this theory is that hepatocytes transiently undergo reprogramming (EMT, or fetal gene expression) as they proliferate.104,108”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [108]

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References 42 · Cited by 148

Research works printed but not linked: 39

  1. [1]Michalopoulos GK Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas Am J Pathol 2010 176 2 13 20019184 PMC2797862
  2. [2]Friedman SL Evolving challenges in hepatic fibrosis Nat Rev Gastroenterol Hepatol 2010 7 425 436 20585339
  3. [3]Michalopoulos GK Hepatostat: Liver regeneration and normal liver tissue maintenance Hepatology 2017 65 1384 1392 27997988
  4. [4]Michelotti GA Xie G Swiderska M Choi SS Karaca G Kruger L Premont R Smoothened is a master regulator of adult liver repair J Clin Invest 2013 123 2380 2394 23563311 PMC3668809
  5. [5]Swiderska-Syn M Syn WK Xie G Kruger L Machado MV Karaca G Michelotti GA Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy Gut 2014 63 1333 1344 24173292 PMC4006344
  6. [6]Higashi T Friedman SL Hoshida Y Hepatic stellate cells as key target in liver fibrosis Adv Drug Deliv Rev 2017 PMC5682243 28506744
  7. [7]Yoshida K Murata M Yamaguchi T Matsuzaki K Okazaki K Reversible Human TGF-beta Signal Shifting between Tumor Suppression and Fibro-Carcinogenesis: Implications of Smad Phospho-Isoforms for Hepatic Epithelial-Mesenchymal Transitions J Clin Med 2016 5 PMC4730132 26771649
  8. [8]Grijalva JL Huizenga M Mueller K Rodriguez S Brazzo J Camargo F Sadri-Vakili G Dynamic alterations in Hippo signaling pathway and YAP activation during liver regeneration Am J Physiol Gastrointest Liver Physiol 2014 307 G196 204 24875096
  9. [9]Herr KJ Tsang YH Ong JW Li Q Yap LL Yu W Yin H Loss of alpha-catenin elicits a cholestatic response and impairs liver regeneration Sci Rep 2014 4 6835 25355493 PMC4213774
  10. [10]Hong L Cai Y Jiang M Zhou D Chen L The Hippo signaling pathway in liver regeneration and tumorigenesis Acta Biochim Biophys Sin (Shanghai) 2015 47 46 52 25476204
  11. [11]Franco DL Mainez J Vega S Sancho P Murillo MM de Frutos CA Del Castillo G Snail1 suppresses TGF-beta-induced apoptosis and is sufficient to trigger EMT in hepatocytes J Cell Sci 2010 123 3467 3477 20930141
  12. [12]Saito K Fukuda N Shinohara K Masuhiro Y Hanazawa S Matsuda H Fujiwara K Modulation of the EMT/MET process by pyrrole-imidazole polyamide targeting human transforming growth factor-beta1 Int J Biochem Cell Biol 2015 66 112 120 26222185
  13. [13]Forte E Chimenti I Rosa P Angelini F Pagano F Calogero A Giacomello A EMT/MET at the Crossroad of Stemness, Regeneration and Oncogenesis: The Ying-Yang Equilibrium Recapitulated in Cell Spheroids Cancers (Basel) 2017 9 PMC5575601 28758926
  14. [14]Taura K Miura K Iwaisako K Osterreicher CH Kodama Y Penz-Osterreicher M Brenner DA Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice Hepatology 2010 51 1027 1036 20052656 PMC2906231
  15. [15]Chu AS Diaz R Hui JJ Yanger K Zong Y Alpini G Stanger BZ Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis Hepatology 2011 53 1685 1695 21520179 PMC3082729
  16. [17]Munker S Wu YL Ding HG Liebe R Weng HL Can a fibrotic liver afford epithelial-mesenchymal transition? World J Gastroenterol 2017 23 4661 4668 28765687 PMC5514631
  17. [18]Wang J Chen F Liu L Qi C Wang B Yan X Huang C Engineering EMT using 3D micro-scaffold to promote hepatic functions for drug hepatotoxicity evaluation Biomaterials 2016 91 11 22 26994875
  18. [19]Nouchi T Tanaka Y Tsukada T Sato C Marumo F Appearance of alpha-smooth-muscle-actin-positive cells in hepatic fibrosis Liver 1991 11 100 105 2051901
  19. [21]Mansuroglu T Dudas J Elmaouhoub A Joza TZ Ramadori G Hepatoblast and mesenchymal cell-specific gene-expression in fetal rat liver and in cultured fetal rat liver cells Histochem Cell Biol 2009 132 11 19 19381675 PMC2693773
  20. [22]Braun L Mead JE Panzica M Mikumo R Bell GI Fausto N Transforming growth factor beta mRNA increases during liver regeneration: a possible paracrine mechanism of growth regulation Proc Natl Acad Sci U S A 1988 3 85 5 1539 43 3422749 PMC279808
  21. [23]Ilani T Alon A Grossman I Horowitz B Kartvelishvily E Cohen SR Fass D A secreted disulfide catalyst controls extracellular matrix composition and function Science 2013 341 74 76 23704371
  22. [24]Patel SH Camargo FD Yimlamai D Hippo Signaling in the Liver Regulates Organ Size, Cell Fate, and Carcinogenesis Gastroenterology 2017 152 533 545 28003097 PMC5285449
  23. [26]Ji WP Dong Y Targeting Yes-associated Protein with Evolved Peptide Aptamers to Disrupt TGF-beta Signaling Pathway: Therapeutic Implication for Bone Tumor Mol Inform 2015 34 771 777 27491038
  24. [27]Szeto SG Narimatsu M Lu M He X Sidiqi AM Tolosa MF Chan L YAP/TAZ Are Mechanoregulators of TGF-beta-Smad Signaling and Renal Fibrogenesis J Am Soc Nephrol 2016 27 3117 3128 26961347 PMC5042658
  25. [28]Piersma B Bank RA Boersema M Signaling in Fibrosis: TGF-beta, WNT, and YAP/TAZ Converge Front Med (Lausanne) 2015 2 59 26389119 PMC4558529
  26. [29]Nishio M Sugimachi K Goto H Wang J Morikawa T Miyachi Y Takano Y Dysregulated YAP1/TAZ and TGF-beta signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice Proc Natl Acad Sci U S A 2016 113 E71 80 26699479 PMC4711826
  27. [30]Swiderska-Syn M Xie G Michelotti GA Jewell ML Premont RT Syn WK2 Diehl AM Hedgehog regulates yes-associated protein 1 in regenerating mouse liver Hepatology 2016 7 64 1 232 44 26970079 PMC4917408
  28. [31]Zhang H von Gise A Liu Q Hu T Tian X He L Pu W Yap1 is required for endothelial to mesenchymal transition of the atrioventricular cushion J Biol Chem 2014 289 18681 18692 24831012 PMC4081914
  29. [32]Ho KJ Bass CE Kroemer AH Ma C Terwilliger E Karp SJ Optimized adeno-associated virus 8 produces hepatocyte-specific Cre-mediated recombination without toxicity or affecting liver regeneration Am J Physiol Gastrointest Liver Physiol 2008 295 G412 419 18535290 PMC2519860
  30. [33]Zheng R Rebolledo-Jaramillo B Zong Y Wang L Russo P Hancock W Stanger BZ Function of GATA factors in the adult mouse liver PLoS One 2013 8 e83723 24367609 PMC3867416
  31. [34]Gunewardena S Walesky C Apte U Global Gene Expression Changes in Liver Following Hepatocyte Nuclear Factor 4 alpha deletion in Adult Mice Genom Data 2015 5 126 128 26120557 PMC4477707
  32. [35]Lee D Le Lay J Kaestner KH The transcription factor CREB has no non-redundant functions in hepatic glucose metabolism in mice Diabetologia 2014 57 1242 1248 24595858
  33. [36]Nakamura I Fernandez-Barrena MG Ortiz-Ruiz MC Almada LL Hu C Elsawa SF Mills LD Activation of the transcription factor GLI1 by WNT signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration J Biol Chem 2013 288 21389 21398 23740243 PMC3774406
  34. [37]Evarts RP Nakatsukasa H Marsden ER Hsia CC Dunsford HA Thorgeirsson SS Cellular and molecular changes in the early stages of chemical hepatocarcinogenesis in the rat Cancer Res 1990 50 3439 3444 1692260
  35. [38]Whittaker S Marais R Zhu AX The role of signaling pathways in the development and treatment of hepatocellular carcinoma Oncogene 2010 29 4989 5005 20639898
  36. [39]Kew MC The role of cirrhosis in the etiology of hepatocellular carcinoma J Gastrointest Cancer 2014 45 12 21 24203525
  37. [40]Hartke J Johnson M Ghabril M The diagnosis and treatment of hepatocellular carcinoma Semin Diagn Pathol 2017 34 153 159 28108047
  38. [41]Huang Q Pu M Zhao G Dai B Bian Z Tang H Chen C Tg737 regulates epithelial-mesenchymal transition and cancer stem cell properties via a negative feedback circuit between Snail and HNF4alpha during liver stem cell malignant transformation Cancer Lett 2017 402 52 60 28536011
  39. [42]Barry ER Camargo FD The Hippo superhighway: signaling crossroads converging on the Hippo/Yap pathway in stem cells and development Curr Opin Cell Biol 2013 25 247 253 23312716

Authors
Oh, S.-H., Swiderska-Syn, M., Jewell, M. L., Premont, R. T., & Diehl, A. M.
Affiliations
Duke University (US)
Corresponding author
Diehl, Anna Mae
ORCID
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2018-08
Volume
69
Issue
2
Pages
359-367
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2018.05.008
PMC
PMC6349217
OpenAlex
W2803790195
Cited by
148
References
42
Citations by year
2026: 7 · 2025: 21 · 2024: 19 · 2023: 24 · 2022: 23 · 2021: 16 · 2020: 20 · 2019: 15 · 2018: 3
FWCI
8.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Hepatology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
NIH (R56 DK106633, R01 DK077794, R37 AA010154)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
liver regeneration, YAP, TGF-beta signaling, epithelial-mesenchymal transition, hepatocytes, partial hepatectomy, liver cirrhosis, Hippo signaling pathway, SNAI1, Smad2, hepatocyte proliferation, myofibroblasts
MeSH terms
YAP-Signaling Proteins, Animals, Liver Regeneration, Phosphoproteins, Signal Transduction, Transforming Growth Factor beta, Mice, Knockout, Cell Cycle Proteins, Hepatocytes, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Epithelial-Mesenchymal Transition

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