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Cited by 289Liver physiology and pathologyPediatric Hepatobiliary Diseases and TreatmentsTissue Engineering and Regenerative Medicine

De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation

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Schaub, Johanna R., Huppert, Kari A., Kurial, Simone N. T., Hsu, Bernadette Y., Cast, Ashley E., Donnelly, Bryan, Karns, Rebekah A., Chen, Feng +7 more·2018·Nature
DOI 10.1038/s41586-018-0075-5PMC PMC6597492
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Abstract

Transdifferentiation is a complete and stable change in cell identity that serves as an alternative to stem-cell-mediated organ regeneration. In adult mammals, findings of transdifferentiation have been limited to the replenishment of cells lost from preexisting structures, in the presence of a fully developed scaffold and niche 1. Here we show that transdifferentiation of hepatocytes in the mouse liver can build a structure that failed to form in development-the biliary system in a mouse model that mimics the hepatic phenotype of human Alagille syndrome (ALGS)2. In these mice, hepatocytes convert into mature cholangiocytes and form bile ducts that are effective in draining bile and persist after the cholestatic liver injury is reversed, consistent with transdifferentiation. These findings redefine hepatocyte plasticity, which appeared to be limited to metaplasia, that is, incomplete and transient biliary differentiation as an adaptation to cell injury, based on previous studies in mice with a fully developed biliary system 3-6. In contrast to bile duct development 7-9, we show that de novo bile duct formation by hepatocyte transdifferentiation is independent of NOTCH signalling. We identify TGFβ signalling as the driver of this compensatory mechanism and show that it is active in some patients with ALGS. Furthermore, we show that TGFβ signalling can be targeted to enhance the formation of the biliary system from hepatocytes, and that the transdifferentiation-inducing signals and remodelling capacity of the bile-duct-deficient liver can be harnessed with transplanted hepatocytes. Our results define the regenerative potential of mammalian transdifferentiation and reveal opportunities for the treatment of ALGS and other cholestatic liver diseases.

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  • Lineage-tracing studies in animal models have confirmed that hepatocytes contribute to bile duct remodeling following cholangiocyte injury.

    “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 [43]

    The Abstract (page unavailable) reports hepatocyte fate tracing in mice: after DDC-induced cholestatic liver injury, hepatocytes gave rise to cells in reactive ductules. It also reports that hepatocytes formed functional peripheral bile ducts in mice lacking those ducts. These findings support a hepatocyte contribution to biliary repair, but the paper does not establish that the reported remodeling followed cholangiocyte injury specifically. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Reprogramming of differentiated cells into progenitor-like cells is an important injury-repair paradigm independent of adult stem cells in various epithelial tissues in mammals.

    “The reprogramming of differentiated cells into progenitor-like cells has recently been discovered as an important injury-repair paradigm independent of adult stem cells in a variety of epithelial tissues in mammals, 1 such as the lung, 2 intestine, 3 pancreas, 4 and liver.5,6”

    From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [6]

    The Abstract (page not provided) describes transdifferentiation as an alternative to stem-cell-mediated regeneration and reports hepatocytes forming mature cholangiocytes during liver injury. It also describes similar cell plasticity in other mammalian epithelia. It does not establish the claimed transition into progenitor-like cells; its demonstrated endpoint is another differentiated cell type. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • Hepatocytes display remarkable plasticity and under some conditions can transdifferentiate into BECs.

    “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 [98]

  • Hepatocyte-to-BEC transdifferentiation can be permanent.

    “This showed that hepatocyte-to-BEC transdifferentiation can be permanent.98”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [98]

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References 55 · Cited by 289

Research works printed but not linked: 47

  1. [2]Vanderpool C Genetic interactions between hepatocyte nuclear factor-6 and Notch signaling regulate mouse intrahepatic bile duct development in vivo. Hepatology 55, 233– 243 (2012). 21898486 PMC3235248
  2. [4]Sekiya S & Suzuki A Hepatocytes, rather than cholangiocytes, can be the major source of primitive ductules in the chronically injured mouse liver. Am J Pathol 184, 1468– 1478 (2014). 24594350
  3. [5]Kamimoto K Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling. Elife 5, e15034 (2016). 27431614 PMC4951195
  4. [6]Tanimizu N Progressive induction of hepatocyte progenitor cells in chronically injured liver. Sci Rep 7, 39990 (2017). 28051157 PMC5209740
  5. [7]Zong Y Notch signaling controls liver development by regulating biliary differentiation. Development 136, 1727– 1739 (2009). 19369401 PMC2673761
  6. [8]Sparks EE, Huppert KA, Brown MA, Washington MK & Huppert SS Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology 51, 1391– 1400 (2010). 20069650 PMC2995854
  7. [9]Jeliazkova P Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1. Hepatology 57, 2469– 2479 (2013). 23315998
  8. [11]Stange DE Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium. Cell 155, 357– 368 (2013). 24120136 PMC4094146
  9. [13]Tetteh PW Replacement of lost Lgr5-positive stem cells through plasticity of their enterocyte-lineage daughters. Cell Stem Cell 18, 203– 213 (2016). 26831517
  10. [14]Van Eyken P, Sciot R & Desmet VJ A cytokeratin immunohistochemical study of cholestatic liver disease: evidence that hepatocytes can express ‘bile duct-type’ cytokeratins. Histopathology 15, 125– 135 (1989). 2476370
  11. [15]Libbrecht L Peripheral bile duct paucity and cholestasis in the liver of a patient with Alagille syndrome: further evidence supporting a lack of postnatal bile duct branching and elongation. Am J Surg Pathol 29, 820– 826 (2005). 15897750
  12. [16]Ernst LM, Spinner NB, Piccoli DA, Mauger J & Russo P Interlobular bile duct loss in pediatric cholestatic disease is associated with aberrant cytokeratin 7 expression by hepatocytes. Pediatr Dev Pathol 10, 383– 390 (2007). 17929991
  13. [17]Fabris L Analysis of liver repair mechanisms in Alagille syndrome and biliary atresia reveals a role for notch signaling. Am J Pathol 171, 641– 653 (2007). 17600123 PMC1934520
  14. [19]Yanger K Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev 27, 719– 724 (2013). 23520387 PMC3639413
  15. [20]Tanimizu N, Nishikawa Y, Ichinohe N, Akiyama H & Mitaka T Sry HMG box protein 9-positive (Sox9+) epithelial cell adhesion molecule-negative (EpCAM-) biphenotypic cells derived from hepatocytes are involved in mouse liver regeneration. J Biol Chem 289, 7589– 7598 (2014). 24482234 PMC3953272
  16. [21]Nagahama Y Contributions of hepatocytes and bile ductular cells in ductular reactions and remodeling of the biliary system after chronic liver injury. Am J Pathol 184, 3001– 3012 (2014). 25193593
  17. [22]Li L Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16, 243– 251 (1997). 9207788
  18. [23]Oda T Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16, 235– 242 (1997). 9207787
  19. [24]McDaniell R NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 79, 169– 173 (2006). 16773578 PMC1474136
  20. [25]Poncy A Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts. Dev Biol 404, 136– 148 (2015). 26033091
  21. [26]Walter TJ, Vanderpool C, Cast AE & Huppert SS Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj. Am J Pathol 184, 1479– 1488 (2014). 24631193 PMC4005980
  22. [27]Gong AY Somatostatin stimulates ductal bile absorption and inhibits ductal bile secretion in mice via SSTR2 on cholangiocytes. Am J Physiol Cell Physiol 284, C1205– 1214 (2003). 12676656
  23. [28]Li B Adult mouse liver contains two distinct populations of cholangiocytes. Stem Cell Reports 9, 478– 489 (2017). 28689996 PMC5549808
  24. [29]Peng L RNA sequencing reveals dynamic changes of mRNA abundance of cytochromes P450 and their alternative transcripts during mouse liver development. Drug Metab Dispos 40, 1198– 1209 (2012). 22434873 PMC3362789
  25. [30]Rezvani M In vivo hepatic reprogramming of myofibroblasts with AAV vectors as a therapeutic strategy for liver fibrosis. Cell Stem Cell 18, 809– 816 (2016). 27257763 PMC5325707
  26. [31]Fiorotto R Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. J Hepatol 59, 124– 130 (2013). 23500150 PMC3777645
  27. [32]Clotman F Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors. Genes Dev 19, 1849– 1854 (2005). 16103213 PMC1186184
  28. [33]Clotman F The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development 129, 1819– 1828 (2002). 11934848
  29. [34]Plumb-Rudewiez N Transcription factor HNF-6/OC-1 inhibits the stimulation of the HNF-3alpha/Foxa1 gene by TGF-beta in mouse liver. Hepatology 40, 1266– 1274 (2004). 15562441
  30. [35]Tanimizu N Intrahepatic bile ducts are developed through formation of homogeneous continuous luminal network and its dynamic rearrangement in mice. Hepatology 64, 175– 188 (2016). 26926046
  31. [36]Rougemont AL Bile ducts in regenerative liver nodules of Alagille patients are not the result of genetic mosaicism. J Pediatr Gastroenterol Nutr 61, 91– 93 (2015). 25643021
  32. [38]Mu X Epithelial transforming growth factor-beta signaling does not contribute to liver fibrosis but protects mice from cholangiocarcinoma. Gastroenterology 150, 720– 733 (2016). 26627606 PMC6490681
  33. [39]Luche H, Weber O, Nageswara Rao T, Blum C & Fehling HJ Faithful activation of an extra-bright red fluorescent protein in “knock-in” Cre-reporter mice ideally suited for lineage tracing studies. Eur J Immunol 37, 43– 53 (2007). 17171761
  34. [40]Yamamoto M A multifunctional reporter mouse line for Cre- and FLP-dependent lineage analysis. Genesis 47, 107– 114 (2009). 19165827 PMC8207679
  35. [41]Lakso M Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. Proc Natl Acad Sci U S A 93, 5860– 5865 (1996). 8650183 PMC39152
  36. [42]Snippert HJ Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143, 134– 144 (2010). 20887898
  37. [43]Levéen P Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood 100, 560– 568 (2002). 12091349
  38. [44]Madisen L A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13, 133– 140 (2010). 20023653 PMC2840225
  39. [45]Shinkai Y RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855– 867 (1992). 1547487
  40. [46]Cao X Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2, 223– 238 (1995). 7697543
  41. [47]Malato Y Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J Clin Invest 121, 4850– 4860 (2011). 22105172 PMC3226005
  42. [48]Raymond CS & Soriano P High-efficiency FLP and PhiC31 site-specific recombination in mammalian cells. PLoS One 2, e162 (2007). 17225864 PMC1764711
  43. [49]Wieser R, Wrana JL & Massagué J GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J 14, 2199– 2208 (1995). 7774578 PMC398326
  44. [51]Dorrell C Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes Dev 25, 1193– 1203 (2011). 21632826 PMC3110957
  45. [52]Chen Z, Wang M, Xiang Q, Sun Z & Zhang R The lectin of Dolichos biflorus agglutinin recognises glycan epitopes on the surface of a subset of cardiac progenitor cells. Cell Biol Int 37, 1238– 1245 (2013). 23881868
  46. [53]Orellana D Calmodulin controls liver proliferation via interactions with C/EBPbeta-LAP and C/EBPbeta-LIP. J Biol Chem 285, 23444– 23456 (2010). 20498378 PMC2906335
  47. [54]Siggs OM, Schnabl B, Webb B & Beutler B X-linked cholestasis in mouse due to mutations of the P4-ATPase ATP11C. Proc Natl Acad Sci U S A 108, 7890– 7895 (2011). 21518881 PMC3093471

Authors
Schaub, J. R., Huppert, K. A., Kurial, S. N. T., Hsu, B. Y., Cast, A. E., Donnelly, B., Karns, R. A., Chen, F., Rezvani, M., Luu, H. Y., Mattis, A. N., Rougemont, A.-L., Rosenthal, P., Huppert, S. S., & Willenbring, H.
Affiliations
  • University of California, San Francisco (US)
  • Cincinnati Children's Hospital Medical Center (US)
  • University Hospital of Geneva (CH)
Corresponding author
  • Huppert, Stacey S.
  • Willenbring, Holger
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2018-05
Volume
557
Issue
7704
Pages
247-251
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-018-0075-5
PMC
PMC6597492
OpenAlex
W2801786525
Cited by
289
References
55
Citations by year
2026: 19 · 2025: 40 · 2024: 33 · 2023: 31 · 2022: 43 · 2021: 42 · 2020: 40 · 2019: 26 · 2018: 14
FWCI
19.11
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Archive ouverte UNIGE (University of Geneva) (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders
  • National Institute of General Medical Sciences (T32GM008568)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107553, R01DK078640, P30DK026743, P30DK078392, T32DK060414)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Surgery › Pediatric Hepatobiliary Diseases and Treatments
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Keywords
hepatocyte transdifferentiation, TGF-beta signaling, cholangiocytes, Alagille syndrome, bile duct formation, Notch signaling, cholestatic liver disease, liver regeneration, cell transplantation, bile duct development
MeSH terms
Animals, Bile Ducts, Biliary Tract, Epithelial Cells, Female, Humans, Male, Mice, Inbred C57BL, Signal Transduction, Transforming Growth Factor beta, Alagille Syndrome, Hepatocytes, Cell Proliferation, Mice, Receptors, Notch, Cell Transdifferentiation

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