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Cited by 138Liver physiology and pathologyTissue Engineering and Regenerative MedicineMesenchymal stem cell research

Bipotent transitional liver progenitor cells contribute to liver regeneration

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Pu, Wenjuan, Zhu, Huan, Zhang, Mingjun, Pikiolek, Monika, Ercan, Caner, Li, Jie, Huang, Xiuzhen, Han, Ximeng +10 more·2023·Nature Genetics
DOI 10.1038/s41588-023-01335-9PMC PMC10101857
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Abstract

Following severe liver injury, when hepatocyte-mediated regeneration is impaired, biliary epithelial cells (BECs) can transdifferentiate into functional hepatocytes. However, the subset of BECs with such facultative tissue stem cell potential, as well as the mechanisms enabling transdifferentiation, remains elusive. Here we identify a transitional liver progenitor cell (TLPC), which originates from BECs and differentiates into hepatocytes during regeneration from severe liver injury. By applying a dual genetic lineage tracing approach, we specifically labeled TLPCs and found that they are bipotent, as they either differentiate into hepatocytes or re-adopt BEC fate. Mechanistically, Notch and Wnt/β-catenin signaling orchestrate BEC-to-TLPC and TLPC-to-hepatocyte conversions, respectively. Together, our study provides functional and mechanistic insights into transdifferentiation-assisted liver regeneration.

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  • When hepatocyte-mediated regeneration is impaired, following chronic injury and induction of hepatocyte senescence, BECs can transdifferentiate into zone 1 hepatocytes which subsequently proliferate and repopulate other lobular zones.

    “When hepatocyte-mediated regeneration is impaired, following chronic injury and induction of hepatocyte senescence, BECs can transdifferentiate into zone 1 hepatocytes which subsequentially proliferate and repopulate other lobular zones[112], [113], [114], [115], [116], [117], [118]”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [112]

    The Main section states that, when hepatocytes become senescent and hepatocyte-mediated regeneration is impaired in mice, BECs can become replication-competent hepatocytes. Results (“Generation of a model for BEC-to-hepatocyte conversion”; page unavailable) place BEC-derived hepatocyte clones near portal veins, but do not show that they subsequently proliferate and repopulate other lobular zones. The zone-to-zone repopulation part is therefore unsupported by this paper. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The appearance of CK19+/HNF4α+ BECs in most human liver disease indications correlates with the degree of hepatocyte senescence.

    “The appearance of CK19+/HNF4α+ BECs in most human liver disease indications correlates with the degree of hepatocyte senescence.112”

    From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [112]

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  1. [1]Stanger BZ Cellular homeostasis and repair in the mammalian liver Annu. Rev. Physiol. 2015 77 179 200 10.1146/annurev-physiol-021113-170255 25668020 PMC5830102 · DOI · Paper page
  2. [2]Gadd VL Aleksieva N Forbes SJ Epithelial plasticity during liver injury and regeneration Cell Stem Cell 2020 27 557 573 10.1016/j.stem.2020.08.016 32971004 · DOI · Paper page
  3. [3]Michalopoulos GK DeFrances MC Liver regeneration Science 1997 276 60 66 10.1126/science.276.5309.60 9082986 · DOI · Paper page
  4. [5]Miyajima A Tanaka M Itoh T Stem/progenitor cells in liver development, homeostasis, regeneration, and reprogramming Cell Stem Cell 2014 14 561 574 10.1016/j.stem.2014.04.010 24792114 · DOI · Paper page
  5. [6]Michalopoulos GK Novel insights into liver homeostasis and regeneration Nat. Rev. Gastroenterol. Hepatol. 2021 18 369 370 10.1038/s41575-021-00454-0 33911225 · DOI
  6. [8]Malato Y Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration J. Clin. Invest. 2011 121 4850 4860 10.1172/JCI59261 22105172 PMC3226005 · DOI · Paper page
  7. [9]Yanger K Adult hepatocytes are generated by self-duplication rather than stem cell differentiation Cell Stem Cell 2014 15 340 349 10.1016/j.stem.2014.06.003 25130492 PMC4505916 · DOI · Paper page
  8. [12]Kamimoto K Heterogeneity and stochastic growth regulation of biliary epithelial cells dictate dynamic epithelial tissue remodeling eLife 2016 5 e15034 10.7554/eLife.15034 27431614 PMC4951195 · DOI
  9. [13]Espanol-Suner R Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice Gastroenterology 2012 143 1564 1575 10.1053/j.gastro.2012.08.024 22922013 · DOI · Paper page
  10. [14]Shin S Upadhyay N Greenbaum LE Kaestner KH Ablation of Foxl1-Cre-labeled hepatic progenitor cells and their descendants impairs recovery of mice from liver injury Gastroenterology 2015 148 192 202 10.1053/j.gastro.2014.09.039 25286440 PMC4387775 · DOI
  11. [18]Russell JO Hepatocyte-specific β-catenin deletion during severe liver injury provokes cholangiocytes to differentiate into hepatocytes Hepatology 2019 69 742 759 10.1002/hep.30270 30215850 PMC6351199 · DOI
  12. [19]Choi TY Ninov N Stainier DY Shin D Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish Gastroenterology 2014 146 776 788 10.1053/j.gastro.2013.10.019 24148620 PMC3943869 · DOI
  13. [20]He J Lu H Zou Q Luo L Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish Gastroenterology 2014 146 789 800 10.1053/j.gastro.2013.11.045 24315993 · DOI
  14. [21]Ko S Hdac1 regulates differentiation of bipotent liver progenitor cells during regeneration via Sox9b and Cdk8 Gastroenterology 2019 156 187 202 10.1053/j.gastro.2018.09.039 30267710 PMC6309465 · DOI
  15. [22]Choi TY Bone morphogenetic protein signaling governs biliary-driven liver regeneration in zebrafish through tbx2b and id2a Hepatology 2017 66 1616 1630 10.1002/hep.29309 28599080 PMC5650528 · DOI
  16. [23]So J Attenuating the epidermal growth factor receptor-extracellular signal-regulated kinase-sex-determining region Y-Box 9 Axis promotes liver progenitor cell-mediated liver regeneration in zebrafish Hepatology 2021 73 1494 1508 10.1002/hep.31437 32602149 PMC7769917 · DOI
  17. [24]Marshall A Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection Gastroenterology 2005 128 33 42 10.1053/j.gastro.2004.09.076 15633121 · DOI
  18. [25]Richardson MM Progressive fibrosis in nonalcoholic steatohepatitis: association with altered regeneration and a ductular reaction Gastroenterology 2007 133 80 90 10.1053/j.gastro.2007.05.012 17631134 · DOI · Paper page
  19. [26]Nobili V Tyrosinemia type 1: metastatic hepatoblastoma with a favorable outcome Pediatrics 2010 126 e235 e238 10.1542/peds.2009-1639 20547648 · DOI
  20. [28]Manning K Al-Dhalimy M Finegold M Grompe M In vivo suppressor mutations correct a murine model of hereditary tyrosinemia type I Proc. Natl Acad. Sci. USA 1999 96 11928 11933 10.1073/pnas.96.21.11928 10518553 PMC18389 · DOI
  21. [30]Means AL Xu Y Zhao A Ray KC Gu G A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs Genesis 2008 46 318 323 10.1002/dvg.20397 18543299 PMC3735352 · DOI
  22. [31]Snippert HJ Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells Cell 2010 143 134 144 10.1016/j.cell.2010.09.016 20887898 · DOI · Paper page
  23. [38]Zong Y Notch signaling controls liver development by regulating biliary differentiation Development 2009 136 1727 1739 10.1242/dev.029140 19369401 PMC2673761 · DOI
  24. [39]Tchorz JS Notch2 signaling promotes biliary epithelial cell fate specification and tubulogenesis during bile duct development in mice Hepatology 2009 50 871 879 10.1002/hep.23048 19551907 · DOI
  25. [40]Jeliazkova P Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1 Hepatology 2013 57 2469 2479 10.1002/hep.26254 23315998 · DOI
  26. [41]Hattoum A Rubin E Orr A Michalopoulos GK Expression of hepatocyte epidermal growth factor receptor, FAS and glypican 3 in EpCAM-positive regenerative clusters of hepatocytes, cholangiocytes, and progenitor cells in human liver failure Hum. Pathol. 2013 44 743 749 10.1016/j.humpath.2012.07.018 23114924 PMC3635113 · DOI
  27. [42]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 2010 51 1391 1400 10.1002/hep.23431 20069650 PMC2995854 · DOI
  28. [43]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. 2014 184 1479 1488 10.1016/j.ajpath.2014.01.030 24631193 PMC4005980 · DOI
  29. [44]Valle-Encinas, E. et al. Canonical Wnt signalling is activated during BEC-to-hepatocyte conversion in vivo and modulates liver epithelial cell plasticity in hepatic organoids. Preprint at bioRxiv10.1101/2020.11.09.374462 (2020).
  30. [45]Boulter L Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease Nat. Med. 2012 18 572 579 10.1038/nm.2667 22388089 PMC3364717 · DOI · Paper page
  31. [47]Okabe H Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice Hepatology 2016 64 1652 1666 10.1002/hep.28774 27533619 PMC5074849 · DOI
  32. [48]Harada N Intestinal polyposis in mice with a dominant stable mutation of the beta-catenin gene EMBO J. 1999 18 5931 5942 10.1093/emboj/18.21.5931 10545105 PMC1171659 · DOI
  33. [49]Russell JO Monga SP Wnt/β-catenin signaling in liver development, homeostasis, and pathobiology Annu Rev. Pathol. 2018 13 351 378 10.1146/annurev-pathol-020117-044010 29125798 PMC5927358 · DOI · Paper page
  34. [50]Sun T ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation Cell Stem Cell 2021 28 1822 1837 10.1016/j.stem.2021.05.013 34129813 · DOI · Paper page
  35. [52]Rodrigo-Torres D The biliary epithelium gives rise to liver progenitor cells Hepatology 2014 60 1367 1377 10.1002/hep.27078 24700364 PMC4410184 · DOI · Paper page
  36. [53]Huch M In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration Nature 2013 494 247 250 10.1038/nature11826 23354049 PMC3634804 · DOI · Paper page
  37. [54]Sackett SD Foxl1 is a marker of bipotential hepatic progenitor cells in mice Hepatology 2009 49 920 929 10.1002/hep.22705 19105206 PMC2931830 · DOI
  38. [55]Shin S Foxl1-Cre-marked adult hepatic progenitors have clonogenic and bilineage differentiation potential Genes Dev. 2011 25 1185 1192 10.1101/gad.2027811 21632825 PMC3110956 · DOI
  39. [56]Evarts RP Nagy P Nakatsukasa H Marsden E Thorgeirsson SS In vivo differentiation of rat liver oval cells into hepatocytes Cancer Res. 1989 49 1541 1547 2466557
  40. [57]Evarts RP Precursor-product relationship between oval cells and hepatocytes: comparison between tritiated thymidine and bromodeoxyuridine as tracers Carcinogenesis 1996 17 2143 2151 10.1093/carcin/17.10.2143 8895481 · DOI
  41. [58]Paku S Schnur J Nagy P Thorgeirsson SS Origin and structural evolution of the early proliferating oval cells in rat liver Am. J. Pathol. 2001 158 1313 1323 10.1016/S0002-9440(10)64082-5 11290549 PMC1891899 · DOI
  42. [59]Lu WY Hepatic progenitor cells of biliary origin with liver repopulation capacity Nat. Cell Biol. 2015 17 971 983 10.1038/ncb3203 26192438 PMC4612439 · DOI · Paper page
  43. [60]Jakubowski A TWEAK induces liver progenitor cell proliferation J. Clin. Invest. 2005 115 2330 2340 10.1172/JCI23486 16110324 PMC1187931 · DOI · Paper page
  44. [61]Limaye PB Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development Lab. Invest. 2008 88 865 872 10.1038/labinvest.2008.56 18574450 PMC2631390 · DOI · Paper page
  45. [62]Isse K Preexisting epithelial diversity in normal human livers: a tissue-tethered cytometric analysis in portal/periportal epithelial cells Hepatology 2013 57 1632 1643 10.1002/hep.26131 23150208 PMC3612393 · DOI
  46. [63]Falkowski O Regeneration of hepatocyte ‘buds’ in cirrhosis from intrabiliary stem cells J. Hepatol. 2003 39 357 364 10.1016/S0168-8278(03)00309-X 12927921 · DOI
  47. [64]Stueck AE Wanless IR Hepatocyte buds derived from progenitor cells repopulate regions of parenchymal extinction in human cirrhosis Hepatology 2015 61 1696 1707 10.1002/hep.27706 25644399 · DOI
  48. [65]Si-Tayeb K Lemaigre FP Duncan SA Organogenesis and development of the liver Dev. Cell 2010 18 175 189 10.1016/j.devcel.2010.01.011 20159590 · DOI · Paper page
  49. [66]Geisler F Strazzabosco M Emerging roles of Notch signaling in liver disease Hepatology 2015 61 382 392 10.1002/hep.27268 24930574 PMC4268103 · DOI
  50. [67]Lu, J. et al. Notch signaling coordinates progenitor cell-mediated biliary regeneration following partial hepatectomy. Sci. Rep.6, 22754 (2016). PMC4782135 26951801
  51. [68]Minnis-Lyons SE Notch-IGF1 signaling during liver regeneration drives biliary epithelial cell expansion and inhibits hepatocyte differentiation Sci. Signal. 2021 14 eaay9185 10.1126/scisignal.aay9185 34158399 · DOI
  52. [70]Jörs S Lineage fate of ductular reactions in liver injury and carcinogenesis J. Clin. Invest. 2015 125 2445 2457 10.1172/JCI78585 25915586 PMC4497753 · DOI · Paper page
  53. [71]Han X Lineage tracing reveals the bipotency of SOX9+ hepatocytes duringliver regeneration Stem Cell Rep. 2019 12 624 638 10.1016/j.stemcr.2019.01.010 PMC6409431 30773487 · DOI · Paper page
  54. [72]Madisen L A robust and high-throughput Cre reporting and characterization system for the whole mouse brain Nat. Neurosci. 2010 13 133 140 10.1038/nn.2467 20023653 PMC2840225 · DOI · Paper page
  55. [73]Madisen L Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance Neuron 2015 85 942 958 10.1016/j.neuron.2015.02.022 25741722 PMC4365051 · DOI · Paper page
  56. [74]Zhang H Endocardium minimally contributes to coronary endothelium in the embryonic ventricular free walls Circ. Res. 2016 118 1880 1893 10.1161/CIRCRESAHA.116.308749 27056912 · DOI
  57. [75]Huelsken J Vogel R Erdmann B Cotsarelis G Birchmeier W beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin Cell 2001 105 533 545 10.1016/S0092-8674(01)00336-1 11371349 · DOI
  58. [76]Han H Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision Int. Immunol. 2002 14 637 645 10.1093/intimm/dxf030 12039915 · DOI
  59. [77]Liu Q Lung regeneration by multipotent stem cells residing at the bronchioalveolar-duct junction Nat. Genet. 2019 51 728 738 10.1038/s41588-019-0346-6 30778223 · DOI
  60. [78]Pu W A genetic system for tissue-specific inhibition of cell proliferation Development 2020 147 dev183830 10.1242/dev.183830 31988189 · DOI
  61. [79]Butler A Hoffman P Smibert P Papalexi E Satija R Integrating single-cell transcriptomic data across different conditions, technologies, and species Nat. Biotechnol. 2018 36 411 420 10.1038/nbt.4096 29608179 PMC6700744 · DOI · Paper page
  62. [80]Becht E Dimensionality reduction for visualizing single-cell data using UMAP Nat. Biotechnol. 2019 37 38 44 10.1038/nbt.4314 30531897 · DOI · Paper page
  63. [81]Zhou Y Metascape provides a biologist-oriented resource for the analysis of systems-level datasets Nat. Commun. 2019 10 1523 10.1038/s41467-019-09234-6 30944313 PMC6447622 · DOI · Paper page
  64. [85]Dobin A STAR: ultrafast universal RNA-seq aligner Bioinformatics 2013 29 15 21 10.1093/bioinformatics/bts635 23104886 PMC3530905 · DOI · Paper page
  65. [86]Liao Y Smyth GK Shi W The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote Nucleic Acids Res. 2013 41 e108 10.1093/nar/gkt214 23558742 PMC3664803 · DOI · Paper page
  66. [87]Love MI Huber W Anders S Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol. 2014 15 550 10.1186/s13059-014-0550-8 25516281 PMC4302049 · DOI · Paper page

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Authors
Pu, W., Zhu, H., Zhang, M., Pikiolek, M., Ercan, C., Li, J., Huang, X., Han, X., Zhang, Z., Lv, Z., Li, Y., Liu, K., He, L., Liu, X., Heim, M. H., Terracciano, L. M., Tchorz, J. S., & Zhou, B.
Affiliations
  • Chinese Academy of Sciences (CN)
  • Novartis (Switzerland) (CH)
  • University Hospital of Basel (CH)
  • University of Chinese Academy of Sciences (CN)
  • Westlake University (CN)
  • University of Basel (CH)
  • Humanitas University (IT)
Corresponding author
  • Tchorz, Jan S.
  • Zhou, Bin
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2023-03-13
Volume
55
Issue
4
Pages
651-664
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-023-01335-9
PMC
PMC10101857
OpenAlex
W4324129275
Cited by
138
References
20
Citations by year
2026: 33 · 2025: 51 · 2024: 35 · 2023: 19
FWCI
23.33
Type
journal article
Language
en
Update notices
correction (2023-04-18)
Open access
Licence
Locations
  • Nature Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Innovative Research Team of High-level Local University in Shanghai
  • Sanofi
  • Vanderbilt University
  • Universität Basel
  • National Natural Science Foundation of China (31900625, 81872241, 31922032, 82088101, 2018YFA0107900, 31730112, 81872241, 32170848, 2020YFA0803202, YSBR-012, 91849202, 32050087, 31922032)
  • Science and Technology Commission of Shanghai Municipality
  • Youth Innovation Promotion Association of the Chinese Academy of Sciences
  • National Institutes of Health
  • Youth Innovation Promotion Association
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
Keywords
liver regeneration, cholangiocytes, transdifferentiation, hepatocyte differentiation, Notch signaling, Wnt/β-catenin signaling, lineage tracing, liver injury
MeSH terms
Cell Differentiation, Epithelial Cells, Liver, Liver Regeneration, Stem Cells, Hepatocytes, Cell Proliferation

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