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Molina LM, Zhu J, Li Q, et al. Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors. Cell Rep. 2021;36(1):109310doi: 10.1016/j.celrep.2021.109310.
Molina, L. M., Zhu, J., Li, Q., Pradhan-Sundd, T., Krutsenko, Y., Sayed, K., Jenkins, N., Vats, R., Bhushan, B., Ko, S., Hu, S., Poddar, M., Singh, S., Tao, J., Sundd, P., Singhi, A., Watkins, S., Ma, X., Benos, P. V., Feranchak, A., Michalopoulos, G., Nejak-Bowen, K., Watson, A., Bell, A., & Monga, S. P. (2021). Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors. Cell reports, 36(1), 109310. https://doi.org/10.1016/j.celrep.2021.109310
Molina, Laura M, et al. "Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors." Cell reports vol. 36,1 (2021): 109310. doi: https://doi.org/10.1016/j.celrep.2021.109310
Molina LM, Zhu J, Li Q, Pradhan-Sundd T, Krutsenko Y, Sayed K, Jenkins N, Vats R, Bhushan B, Ko S, Hu S, Poddar M, Singh S, Tao J, Sundd P, Singhi A, Watkins S, Ma X, Benos PV, Feranchak A, Michalopoulos G, Nejak-Bowen K, Watson A, Bell A, Monga SP. Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors. Cell Rep. 2021 Jul 06;36(1):109310. doi: 10.1016/j.celrep.2021.109310. PMID: 34233187; PMCID: PMC8280534.
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Cell Rep. 2021 Jul 06;36(1):109310. doi: 10.1016/j.celrep.2021.109310.

Compensatory hepatic adaptation accompanies permanent absence of intrahepatic biliary network due to YAP1 loss in liver progenitors.

Cell reports

Laura M Molina, Junjie Zhu, Qin Li, Tirthadipa Pradhan-Sundd, Yekaterina Krutsenko, Khaled Sayed, Nathaniel Jenkins, Ravi Vats, Bharat Bhushan, Sungjin Ko, Shikai Hu, Minakshi Poddar, Sucha Singh, Junyan Tao, Prithu Sundd, Aatur Singhi, Simon Watkins, Xiaochao Ma, Panayiotis V Benos, Andrew Feranchak, George Michalopoulos, Kari Nejak-Bowen, Alan Watson, Aaron Bell, Satdarshan P Monga

Affiliations

  1. Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  2. Department of Pharmaceutical Sciences and Center for Pharmacogenetics, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
  3. Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA.
  4. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA.
  5. Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  6. Department of Computational and Systems Biology, University of Pittsburgh, 3420 Forbes Ave, Pittsburgh, PA 15213, USA; Biomedical Engineering and Systems, Faculty of Engineering, Cairo University, Giza, Egypt.
  7. Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA.
  8. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA; Department of Bioengineering, School of Engineering, University of Pittsburgh, Pittsburgh, PA, USA.
  9. Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA.
  10. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA.
  11. Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA.
  12. Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  13. Department of Computational and Systems Biology, University of Pittsburgh, 3420 Forbes Ave, Pittsburgh, PA 15213, USA.
  14. Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA.
  15. Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Pittsburgh Liver Research Center, University of Pittsburgh and UPMC, Pittsburgh, PA, USA; Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine and UPMC, Pittsburgh, PA, USA. Electronic address: [email protected].

PMID: 34233187 PMCID: PMC8280534 DOI: 10.1016/j.celrep.2021.109310

Abstract

Yes-associated protein 1 (YAP1) regulates cell plasticity during liver injury, regeneration, and cancer, but its role in liver development is unknown. We detect YAP1 activity in biliary cells and in cells at the hepatobiliary bifurcation in single-cell RNA sequencing analysis of developing livers. Deletion of Yap1 in hepatoblasts does not impair Notch-driven SOX9+ ductal plate formation but does prevent the formation of the abutting second layer of SOX9+ ductal cells, blocking the formation of a patent intrahepatic biliary tree. Intriguingly, these mice survive for 8 months with severe cholestatic injury and without hepatocyte-to-biliary transdifferentiation. Ductular reaction in the perihilar region suggests extrahepatic biliary proliferation, likely seeking the missing intrahepatic biliary network. Long-term survival of these mice occurs through hepatocyte adaptation via reduced metabolic and synthetic function, including altered bile acid metabolism and transport. Overall, we show YAP1 as a key regulator of bile duct development while highlighting a profound adaptive capability of hepatocytes.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Keywords: 3D-tissue clearing and imaging; Hippo signaling; bile acid metabolism; bile duct development; intrahepatic bile duct; intravital microscopy; liver adaptation; liver development; liver regeneration

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

  1. Hepatology. 2016 Feb;63(2):550-65 - PubMed
  2. Hepatology. 1984 Jul-Aug;4(4):691-8 - PubMed
  3. Hum Mol Genet. 2020 Nov 4;29(18):3064-3080 - PubMed
  4. Gastroenterology. 2018 Mar;154(4):1080-1095 - PubMed
  5. Hepatol Commun. 2020 Jan 22;4(3):387-398 - PubMed
  6. Annu Rev Pathol. 2020 Jan 24;15:1-22 - PubMed
  7. Biochim Biophys Acta Mol Basis Dis. 2018 Apr;1864(4 Pt B):1245-1253 - PubMed
  8. Nat Commun. 2016 Jun 30;7:11961 - PubMed
  9. Gastroenterology. 2013 Jun;144(7):1530-1542.e12 - PubMed
  10. Cell. 2014 Jun 5;157(6):1324-1338 - PubMed
  11. Gastroenterology. 2014 Sep;147(3):690-701 - PubMed
  12. Nature. 2018 Aug;560(7719):494-498 - PubMed
  13. J Hepatol. 2018 May;68(5):1049-1062 - PubMed
  14. Mol Cancer Res. 2007 Nov;5(11):1159-70 - PubMed
  15. Cell Stem Cell. 2019 Jul 3;25(1):23-38.e8 - PubMed
  16. BMC Bioinformatics. 2013 Apr 15;14:128 - PubMed
  17. Gastroenterology. 2017 Feb;152(3):533-545 - PubMed
  18. Curr Protoc Cytom. 2018 Oct;86(1):e38 - PubMed
  19. Oncotarget. 2015 Apr 30;6(12):10102-15 - PubMed
  20. Hepatology. 2016 Nov;64(5):1711-1724 - PubMed
  21. Lab Anim. 2010 Oct;44(4):373-6 - PubMed
  22. PLoS One. 2017 Jul 7;12(7):e0180486 - PubMed
  23. Oncogene. 2018 Jun;37(24):3229-3242 - PubMed
  24. Hepatology. 2016 Nov;64(5):1652-1666 - PubMed
  25. Bioinformatics. 2004 Feb 12;20(3):307-15 - PubMed
  26. J Appl Physiol. 1965 May;20(3):534-7 - PubMed
  27. Sci Rep. 2017 Aug 30;7(1):9967 - PubMed
  28. Nat Biotechnol. 2016 May;34(5):525-7 - PubMed
  29. Hepatology. 2005 Mar;41(3):535-44 - PubMed
  30. J Clin Invest. 2017 Jan 3;127(1):137-152 - PubMed
  31. Hepatology. 2008 May;47(5):1667-79 - PubMed
  32. Nature. 2013 May 16;497(7449):332-7 - PubMed
  33. Hepatology. 1999 Mar;29(3):822-9 - PubMed
  34. Chem Res Toxicol. 2018 Jul 16;31(7):548-555 - PubMed
  35. Nucleic Acids Res. 2015 Apr 20;43(7):e47 - PubMed
  36. Cell Rep. 2014 Oct 9;9(1):261-271 - PubMed
  37. BMC Bioinformatics. 2007 Feb 08;8:48 - PubMed
  38. Gastroenterology. 2007 Jan;132(1):415-31 - PubMed
  39. Cell. 2015 Dec 3;163(6):1500-14 - PubMed
  40. Nat Methods. 2012 Jun 28;9(7):676-82 - PubMed
  41. Genes Dev. 2013 Apr 1;27(7):719-24 - PubMed
  42. J Clin Invest. 2015 Jan;125(1):386-402 - PubMed
  43. Cell. 2014 Apr 24;157(3):726-39 - PubMed
  44. J Vis Exp. 2012 Oct 25;(68):e4272 - PubMed
  45. Genesis. 2000 Feb;26(2):149-50 - PubMed
  46. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 - PubMed
  47. Lab Invest. 2017 Jul;97(7):843-853 - PubMed
  48. Int J Mol Sci. 2018 Nov 29;19(12): - PubMed
  49. Semin Cell Dev Biol. 2017 Jun;66:43-50 - PubMed
  50. J Pediatr Gastroenterol Nutr. 2010 May;50(5):526-30 - PubMed
  51. J Biol Chem. 2012 Aug 17;287(34):28586-97 - PubMed
  52. Gut. 2001 Sep;49(3):431-5 - PubMed
  53. J Lipid Res. 1989 May;30(5):719-30 - PubMed
  54. IEEE Trans Pattern Anal Mach Intell. 2017 Nov;39(11):2227-2241 - PubMed
  55. Gastroenterology. 2018 Oct;155(4):1218-1232.e24 - PubMed
  56. Hepatology. 2021 May;73(5):2005-2022 - PubMed
  57. Hepatology. 2017 Nov;66(5):1387-1401 - PubMed
  58. Nat Biotechnol. 2014 Apr;32(4):381-386 - PubMed
  59. Genes Dev. 2005 Aug 15;19(16):1849-54 - PubMed
  60. Cell. 2019 Jun 13;177(7):1888-1902.e21 - PubMed
  61. Am J Pathol. 2014 May;184(5):1479-88 - PubMed
  62. Nucleic Acids Res. 2016 Jul 8;44(W1):W90-7 - PubMed
  63. Oncotarget. 2019 Feb 19;10(15):1475-1490 - PubMed
  64. Cell Rep. 2015 Mar 17;10(10):1692-1707 - PubMed
  65. BMC Genomics. 2017 Dec 04;18(1):946 - PubMed
  66. Bioinformatics. 2009 Aug 15;25(16):2078-9 - PubMed
  67. Clin Liver Dis. 2018 Nov;22(4):625-641 - PubMed
  68. Nature. 2005 Jun 16;435(7044):944-7 - PubMed
  69. Gastroenterology. 2009 Jun;136(7):2325-33 - PubMed
  70. Dev Cell. 2010 Jul 20;19(1):27-38 - PubMed
  71. Am J Pathol. 2014 May;184(5):1468-78 - PubMed
  72. Nature. 2018 May;557(7704):247-251 - PubMed
  73. Ann Hepatol. 2017 Oct 28;16(Suppl. 1: s3-105.):s53-s57 - PubMed

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