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Massive rearrangements of cellular MicroRNA signatures are key drivers of hepatocyte dedifferentiation

Lauschke, Volker M., Vorrink, Sabine U., Moro, Sabrina M.L., Rezayee, Fatemah, Nordling, Åsa, Hendriks, Delilah F.G., Bell, Catherine C., Sison‐Young, Rowena +7 more·2016·Hepatology
DOI 10.1002/hep.28780
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Abstract

Hepatocytes are dynamic cells that, upon injury, can alternate between nondividing differentiated and dedifferentiated proliferating states in vivo . However, in two‐dimensional cultures, primary human hepatocytes (PHHs) rapidly dedifferentiate, resulting in loss of hepatic functions that significantly limits their usefulness as an in vitro model of liver biology, liver diseases, as well as drug metabolism and toxicity. Thus, understanding the underlying mechanisms and stalling of the dedifferentiation process would be highly beneficial to establish more‐accurate and relevant long‐term in vitro hepatocyte models. Here, we present comprehensive analyses of whole proteome and transcriptome dynamics during the initiation of dedifferentiation during the first 24 hours of culture. We report that early major rearrangements of the noncoding transcriptome, hallmarked by increased expression of small nucleolar RNAs, long noncoding RNAs, microRNAs (miRNAs), and ribosomal genes, precede most changes in coding genes during dedifferentiation of PHHs, and we speculated that these modulations could drive the hepatic dedifferentiation process. To functionally test this hypothesis, we globally inhibited the miRNA machinery using two established chemically distinct compounds, acriflavine and poly‐ l ‐lysine. These inhibition experiments resulted in a significantly impaired miRNA response and, most important, in a pronounced reduction in the down‐regulation of hepatic genes with importance for liver function. Thus, we provide strong evidence for the importance of noncoding RNAs, in particular, miRNAs, in hepatic dedifferentiation, which can aid the development of more‐efficient differentiation protocols for stem‐cell‐derived hepatocytes and broaden our understanding of the dynamic properties of hepatocytes with respect to liver regeneration. Conclusion: miRNAs are important drivers of hepatic dedifferentiation, and our results provide valuable information regarding the mechanisms behind liver regeneration and possibilities to inhibit dedifferentiation in vitro . (H epatology 2016;64:1743‐1756)

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Research works printed but not linked: 38

  1. Yovchev MI, Grozdanov PN, Zhou H, Racherla H, Guha C, Dabeva MD, et al. Identification of adult hepatic progenitor cells capable of repopulating injured rat liver. HEPATOLOGY 2007;47: 636-647.
  2. Kordes C, H€ aussinger D. Hepatic stem cell niches. J Clin Invest 2013;123:1874-1880.
  3. Evarts RP, Nagy P, Marsden E, Thorgeirsson SS. A precursor- product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis 1987;8:1737-1740.
  4. Yanger K, Knigin D, Zong Y, Maggs L, Gu G, Akiyama H, et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 2014;15:340-349.
  5. Yanger K, Zong Y, Maggs LR, Shapira SN, Maddipati R, Aiello NM, et al. Robust cellular reprogramming occurs sponta- neously during liver regeneration. Genes Dev 2013;27:719-724.
  6. Chen Y, Wong PP, Sjeklocha L, Steer CJ, Sahin MB. Mature hepatocytes exhibit unexpected plasticity by direct dedifferentia- tion into liver progenitor cells in culture. HEPATOLOGY 2012;55: 563-574.
  7. Rowe C, Gerrard DT, Jenkins R, Berry A, Durkin K, Sundstrom L, et al. Proteome-wide analyses of human hepato- cytes during differentiation and dedifferentiation. HEPATOLOGY 2013;58:799-809.
  8. Baker TK, Carfagna MA, Gao H, Dow ER, Li Q, Searfoss GH, Ryan TP, et al. Temporal gene expression analysis of monolayer cultured rat hepatocytes. Chem Res Toxicol 2001;14: 1218-1231.
  9. Cech TR, Steitz JA. The noncoding RNA revolution-trashing old rules to forge new ones. Cell 2014;157:77-94.
  10. Wilczynska A, Bushell M. The complexity of miRNA-mediated repression. Cell Death Differ 2015;22:22-33.
  11. Gamazon ER, Innocenti F, Wei R, Wang L, Zhang M, Mirkov S, et al. A genome-wide integrative study of microRNAs in human liver. BMC Genomics 2013;14:395.
  12. Kim N, Kim H, Jung I, Kim Y, Kim D, Han YM, et al. Expres- sion profiles of miRNAs in human embryonic stem cells during hepatocyte differentiation. Hepatol Res 2011;41:170-183.
  13. Clouet d'Orval B, Bortolin ML, Gaspin C, Bachellerie JP. Box C/D RNA guides for the ribose methylation of archaeal tRNAs. The tRNATrp intron guides the formation of two ribose- methylated nucleosides in the mature tRNATrp. Nucleic Acids Res 2011;29:4518-4529.
  14. Decatur WA, Fournier MJ. rRNA modifications and ribosome function. Trends Biochem Sci 2002;27:344-351.
  15. Taft RJ, Glazov EA, Lassmann T, Hayashizaki Y, Carninci P, Mattick JS, et al. Small RNAs derived from snoRNAs. RNA 2009;15:1233-1240.
  16. Kishore S, Kanna A, Zhang Z, Hui J, Balwierz PJ, Stefan M, et al. The snoRNA MBII-52 (SNORD 115) is processed into smaller RNAs and regulates alternative splicing. Hum Mol Genet 2010;19:1153-1164.
  17. Ender C, Krek A, Friedl€ ander MR, Beitzinger M, Weinmann L, Chen W, et al. A Human snoRNA with microRNA-like functions. Mol Cell 2008;32:519-528.
  18. Sharma E, Sterne-Weiler T, O'Hanlon D, Blencowe BJ. Global mapping of human RNA-RNA interactions. Mol Cell 2016;62: 618-626.
  19. Kung JT, Colognori D, Lee JT. Long noncoding RNAs: past, present, and future. Genetics 2013;193:651-669.
  20. Strom SC, Pisarov LA, Dorko K, Thompson MT, Schuetz JD, Schuetz EG, et al. Use of human hepatocytes to study P450 gene induction. Methods Enzymol 1996;272:388-401.
  21. Yang J, Liao M, Shou M, Jamei M, Rowland Yeo K, Tucker GT, Rostami-Hodjegan A, et al. Cytochrome p450 turnover: regulation of synthesis and degradation, methods for determining rates, and implications for the prediction of drug interactions. Curr Drug Metab 2008;9:384-394.
  22. Watashi K, Yeung ML, Starost MF, Hosmane RS, Jeang KT. Identification of small molecules that suppress microRNA function and reverse tumorigenesis. J Biol Chem 2010;285: 24707-24716.
  23. John K, Hadem J, Krech T, Wahl K, Manns MP, Dooley S, et al. MicroRNAs play a role in spontaneous recovery from acute liver failure. HEPATOLOGY 2014;60:1346-1355.
  24. Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, et al. miR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 2008;27:5651-5661.
  25. Cirera-Salinas D, Pauta M, Allen RM, Salerno AG, Ramirez CM, Chamorro-Jorganes A, et al. Mir-33 regulates cell prolifera- tion and cell cycle progression. Cell Cycle 2012;11:922-933.
  26. Zhang SY, Surapureddi S, Coulter S, Ferguson SS, Goldstein JA. Human CYP2C8 is post-transcriptionally regulated by microRNAs 103 and 107 in human liver. Mol Pharmacol 2012;82:529-540.
  27. Azimifar SB, Nagaraj N, Cox J, Mann M. Cell-type-resolved quantitative proteomics of murine liver. Cell Metab 2014;20: 1076-1087.
  28. Xiao L, Grove A. Coordination of ribosomal protein and ribo- somal RNA gene expression in response to TOR signaling. Curr Genomics 2009;10:198-205.
  29. Kimball SR. Eukaryotic initiation factor eIF2. Int J Biochem Cell Biol 1999;31:25-29.
  30. Diederichs S, Haber DA. Dual role for argonautes in microRNA processing and posttranscriptional regulation of microRNA expression. Cell 2007;131:1097-1108.
  31. Gantier MP, McCoy CE, Rusinova I, Saulep D, Wang D, Xu D, et al. Analysis of microRNA turnover in mammalian cells fol- lowing Dicer1 ablation. Nucleic Acids Res 2011;39:5692-5703.
  32. Olejniczak SH, La Rocca G, Gruber JJ, Thompson CB. Long- lived microRNA-Argonaute complexes in quiescent cells can be activated to regulate mitogenic responses. Proc Natl Acad Sci U S A 2013;110:157-162.
  33. Runge DM, Runge D, Dorko K, Pisarov LA, Leckel K, Kostrubsky VE, et al. Epidermal growth factor-and hepatocyte growth factor-receptor activity in serum-free cultures of human hepatocytes. J Hepatol 1999;30:265-274.
  34. Yu D, Green B, Marrone A, Guo Y, Kadlubar S, Lin D, et al. Suppression of CYP2C9 by microRNA hsa-miR-128-3p in human liver cells and association with hepatocellular carcinoma. Sci Rep 2015;5:8534-8539.
  35. Wei Z, Jiang S, Zhang Y, Wang X, Peng X, Meng C, et al. The effect of microRNAs in the regulation of human CYP3A4: a sys- tematic study using a mathematical model. Sci Rep 2014;4:1-7.
  36. Li Z, Rana TM. Therapeutic targeting of microRNAs: current status and future challenges. Nat Genet 2014;13:622-638.
  37. Schug J, McKenna LB, Walton G, Hand N, Mukherjee S, Essuman K, et al. Dynamic recruitment of microRNAs to their mRNA targets in the regenerating liver. BMC Genomics 2013; 14:264.
  38. Godoy P, Hengstler JG, Ilkavets I, Meyer C, Bachmann A, M€ uller A, et al. Extracellular matrix modulates sensitivity of hepatocytes to fibroblastoid dedifferentiation and transforming growth factor b- induced apoptosis. HEPATOLOGY 2009;49:2031-2043.

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Authors
Lauschke, V. M., Vorrink, S. U., Moro, S. M. L., Rezayee, F., Nordling, Å., Hendriks, D. F. G., Bell, C. C., Sison‐Young, R., Park, B. K., Goldring, C. E., Ellis, E., Johansson, I., Mkrtchian, S., Andersson, T. B., & Ingelman‐Sundberg, M.
Affiliations
  • Section of Pharmacogenetics, Department of Physiology and Pharmacology,Karolinska Institutet,Stockholm,Sweden
  • MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology,University of Liverpool,Liverpool,UK
  • Department of Clinical Science, Intervention and Technology,Karolinska University Hospital Huddinge,Karolinska Institutet,Stockholm,Sweden
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2016-09-30
Volume
64
Issue
5
Pages
1743-1756
ISSN
  • 0270-9139
  • 1527-3350
DOI
10.1002/hep.28780
Cited by
113
References
7
Language
en
Licence

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