Appropriate expression of P57kip2 drives trophoblast fusion via cell cycle arrest

in Reproduction
Authors:
Hong-Lan Song Department of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing, China

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Tai-Hang Liu The Joint International Research Laboratory of Reproduction and Development, Ministry of Education, Chongqing, China
Department of Bioinformatics, School of Basic Medicine, Chongqing Medical University, Chongqing, China

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Yong-Heng Wang The Joint International Research Laboratory of Reproduction and Development, Ministry of Education, Chongqing, China

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Fang-Fang Li The Joint International Research Laboratory of Reproduction and Development, Ministry of Education, Chongqing, China

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Ling-Ling Ruan Department of Herbal Medicine, School of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China

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Enoch Appiah Adu-Gyamfi The Joint International Research Laboratory of Reproduction and Development, Ministry of Education, Chongqing, China

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Si-Chen Hu Department of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing, China

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Xue-Mei Chen Department of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
The Joint International Research Laboratory of Reproduction and Development, Ministry of Education, Chongqing, China

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Yu-Bin Ding Department of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing, China
The Joint International Research Laboratory of Reproduction and Development, Ministry of Education, Chongqing, China

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Li-Juan Fu The Joint International Research Laboratory of Reproduction and Development, Ministry of Education, Chongqing, China
Department of Herbal Medicine, School of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
Department of Herbal Medicine, School of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China

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Correspondence should be addressed to L-J Fu; Email: fulijuan@cqmu.edu.cn

*(H-L Song and T-H Liu contributed equally to this work)

DOI:
https://doi.org/10.1530/REP-20-0638
Volume/Issue:
Volume 161: Issue 6
Page Range:
633–644
Article Type:
Research Article
Online Publication Date:
05 May 2021
Copyright:
© 2021 Society for Reproduction and Fertility 2021
Restricted access
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The syncytiotrophoblast, derived from cytotrophoblast fusion, is responsible for maternal–fetal exchanges, secretion of pregnancy-related hormones, and fetal defense against pathogens. Inadequate cytotrophoblast fusion can lead to pregnancy disorders, such as preeclampsia and fetal growth restriction. However, little is known about the mechanism of cytotrophoblast fusion in both physiological and pathological pregnancy conditions. In this study, P57kip2 (P57), a cell cycle-dependent kinase inhibitor that negatively regulates the cell cycle, was found to be up-regulated during the process of syncytialization in both primary trophoblast cells and BeWo cells. Co-immunofluorescence with proliferation markers Ki67 and Cyclin-CDK factors further showed that P57 specifically localizes in the post-mitotic cytotrophoblast subtype of the early pregnancy villi. Overexpression of P57 promoted trophoblast syncytialization by arresting the cell cycle at the G1/G0 phase and inhibiting proliferation. Blocking of the cell cycle through a serum starvation culture resulted in an enhancement of cytotrophoblast fusion and the up-regulation of P57. In both spontaneous cytotrophoblast fusion and forskolin-induced BeWo cell fusion models, an initial up-regulation of P57 was observed followed by a subsequent down-regulation. These findings indicate that proper expression of P57 at cytotrophoblast differentiation nodes plays an important role in trophoblast syncytialization.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

  • Aghababaei M, Hogg K, Perdu S, Robinson WP & Beristain AG 2015 ADAM12-directed ectodomain shedding of E-cadherin potentiates trophoblast fusion. Cell Death and Differentiation 22 1970–1984. (https://doi.org/10.1038/cdd.2015.44)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Aguilar PS, Baylies MK, Fleissner A, Helming L, Inoue N, Podbilewicz B, Wang H & Wong M 2013 Genetic basis of cell-cell fusion mechanisms. Trends in Genetics 29 427–437. (https://doi.org/10.1016/j.tig.2013.01.011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bainbridge SA, Minhas A, Whiteley KJ, Qu D, Sled JG, Kingdom JC & Adamson SL 2012 Effects of reduced Gcm1 expression on trophoblast morphology, fetoplacental vascularity, and pregnancy outcomes in mice. Hypertension 59 732–739. (https://doi.org/10.1161/HYPERTENSIONAHA.111.183939)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Besson A, Dowdy SF & Roberts JM 2008 CDK inhibitors: cell cycle regulators and beyond. Developmental Cell 14 159–169. (https://doi.org/10.1016/j.devcel.2008.01.013)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Burdon T, Smith A & Savatier P 2002 Signalling, cell cycle and pluripotency in embryonic stem cells. Trends in Cell Biology 12 432–438. (https://doi.org/10.1016/s0962-8924(0202352-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Burton GJ & Fowden AL 2015 The placenta: a multifaceted, transient organ. Philosophical Transactions of the Royal Society of London: Series B, Biological Sciences 370 20140066. (https://doi.org/10.1098/rstb.2014.0066)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chen EH & Olson EN 2005 Unveiling the mechanisms of cell-cell fusion. Science 308 369–373. (https://doi.org/10.1126/science.1104799)

  • Chong JL, Wenzel PL, Saenz-Robles MT, Nair V, Ferrey A, Hagan JP, Gomez YM, Sharma N, Chen HZ & Ouseph M et al.2009 E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells. Nature 462 930–934. (https://doi.org/10.1038/nature08677)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chuprin A, Gal H, Biron-Shental T, Biran A, Amiel A, Rozenblatt S & Krizhanovsky V 2013 Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes and Development 27 2356–2366. (https://doi.org/10.1101/gad.227512.113)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cordeiro A, Neto AP, Carvalho F, Ramalho C & Doria S 2014 Relevance of genomic imprinting in intrauterine human growth expression of CDKN1C, H19, IGF2, KCNQ1 and PHLDA2 imprinted genes. Journal of Assisted Reproduction and Genetics 31 1361–1368. (https://doi.org/10.1007/s10815-014-0278-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Creff J & Besson A 2020 Functional versatility of the CDK inhibitor p57(Kip2). Frontiers in Cell and Developmental Biology 8 584590. (https://doi.org/10.3389/fcell.2020.584590)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cvitic S, Longtine MS, Hackl H, Wagner K, Nelson MD, Desoye G & Hiden U 2013 The human placental sexome differs between trophoblast epithelium and villous vessel endothelium. PLoS ONE 8 e79233. (https://doi.org/10.1371/journal.pone.0079233)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gal H, Lysenko M, Stroganov S, Vadai E, Youssef SA, Tzadikevitch-Geffen K, Rotkopf R, Biron-Shental T, De Bruin A & Neeman M et al.2019 Molecular pathways of senescence regulate placental structure and function. EMBO Journal 38 e100849. (https://doi.org/10.15252/embj.2018100849)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gill M, Motta-Mejia C, Kandzija N, Cooke W, Zhang W, Cerdeira AS, Bastie C, Redman C & Vatish M 2019 Placental syncytiotrophoblast-derived extracellular vesicles carry active NEP (neprilysin) and are increased in preeclampsia. Hypertension 73 1112–1119. (https://doi.org/10.1161/HYPERTENSIONAHA.119.12707)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gomez-Lamarca MJ, Cobreros-Reguera L, Ibanez-Jimenez B, Palacios IM & Martin-Bermudo MD 2014 Integrins regulate epithelial cell differentiation by modulating Notch activity. Journal of Cell Science 127 4667–4678. (https://doi.org/10.1242/jcs.153122)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Halevy O, Novitch BG, Spicer DB, Skapek SX, Rhee J, Hannon GJ, Beach D & Lassar AB 1995 Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science 267 1018–1021. (https://doi.org/10.1126/science.7863327)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ishihara N, Matsuo H, Murakoshi H, Laoag-Fernandez JB, Samoto T & Maruo T 2002 Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation. American Journal of Obstetrics and Gynecology 186 158–166. (https://doi.org/10.1067/mob.2002.119176)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Iyer VR, Eisen MB, Ross DT, Schuler G, Moore T, Lee JC, Trent JM, Staudt LM, Hudson Jr J & Boguski MS et al.1999 The transcriptional program in the response of human fibroblasts to serum. Science 283 83–87. (https://doi.org/10.1126/science.283.5398.83)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jiang Y, Lo W, Akhmametyeva EM & Chang LS 2006 Over-expression of p73beta results in apoptotic death of post-mitotic hNT neurons. Journal of the Neurological Sciences 240 1–6. (https://doi.org/10.1016/j.jns.2005.08.012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kavanagh E, Vlachos P, Emourgeon V, Rodhe J & Joseph B 2012 p57(KIP2) control of actin cytoskeleton dynamics is responsible for its mitochondrial pro-apoptotic effect. Cell Death and Disease 3 e311. (https://doi.org/10.1038/cddis.2012.51)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kellam P & Weiss RA 2019 Protecting fetal development. Science 365 118–119. (https://doi.org/10.1126/science.aay2054)

  • Kohli S, Hoffmann J, Lochmann F, Markmeyer P, Huebner H, Fahlbusch FB, Al-Dabet MM, Gadi I, Manoharan J & Lottge M et al.2017 p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction. Cell Death and Disease 8 e2730. (https://doi.org/10.1038/cddis.2017.127)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A & Harlow E 1997 New functional activities for the p21 family of CDK inhibitors. Genes and Development 11 847–862. (https://doi.org/10.1101/gad.11.7.847)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Larsson LI, Bjerregaard B & Talts JF 2008 Cell fusions in mammals. Histochemistry and Cell Biology 129 551–561. (https://doi.org/10.1007/s00418-008-0411-1)

  • Liu Y, Fan X, Wang R, Lu X, Dang YL, Wang H, Lin HY, Zhu C, Ge H & Cross JC et al.2018 Single-cell RNA-seq reveals the diversity of trophoblast subtypes and patterns of differentiation in the human placenta. Cell Research 28 819–832. (https://doi.org/10.1038/s41422-018-0066-y)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lu X, Wang R, Zhu C, Wang H, Lin HY, Gu Y, Cross JC & Wang H 2017 Fine-tuned and cell-cycle-restricted expression of fusogenic protein Syncytin-2 maintains functional placental syncytia. Cell Reports 21 1150–1159. (https://doi.org/10.1016/j.celrep.2017.10.019)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Maltepe E & Fisher SJ 2015 Placenta: the forgotten organ. Annual Review of Cell and Developmental Biology 31 523–552. (https://doi.org/10.1146/annurev-cellbio-100814-125620)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • McNamara GI, Davis BA, Dwyer DM, John RM & Isles AR 2016 Behavioural abnormalities in a novel mouse model for Silver Russell syndrome. Human Molecular Genetics 25 5407–5417. (https://doi.org/10.1093/hmg/ddw357)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mi S, Lee X, Li X, Veldman GM, Finnerty H, Racie L, Lavallie E, Tang XY, Edouard P & Howes S et al.2000 Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 403 785–789. (https://doi.org/10.1038/35001608)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Newhouse SM, Davidge ST, Winkler-Lowen B, Demianczuk N & Guilbert LJ 2007 In vitro differentiation of villous trophoblasts from pregnancies complicated by intrauterine growth restriction with and without pre-eclampsia. Placenta 28 999–1003. (https://doi.org/10.1016/j.placenta.2007.04.008)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ockleford CD & Whyte A 1977 Differeniated regions of human placental cell surface associated with exchange of materials between maternal and foetal blood: coated vesicles. Journal of Cell Science 25 293–312.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Okae H, Toh H, Sato T, Hiura H, Takahashi S, Shirane K, Kabayama Y, Suyama M, Sasaki H & Arima T 2018 Derivation of human trophoblast stem cells. Cell Stem Cell 22 50–63.e6. (https://doi.org/10.1016/j.stem.2017.11.004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pateras IS, Apostolopoulou K, Niforou K, Kotsinas A & Gorgoulis VG 2009 p57KIP2: ‘Kip’ing the cell under control. Molecular Cancer Research 7 1902–1919. (https://doi.org/10.1158/1541-7786.MCR-09-0317)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Posey SC & Bierer BE 1999 Actin stabilization by jasplakinolide enhances apoptosis induced by cytokine deprivation. Journal of Biological Chemistry 274 4259–4265. (https://doi.org/10.1074/jbc.274.7.4259)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Robbins JR, Skrzypczynska KM, Zeldovich VB, Kapidzic M & Bakardjiev AI 2010 Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes. PLoS Pathogens 6 e1000732. (https://doi.org/10.1371/journal.ppat.1000732)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Robinson JF, Kapidzic M, Gormley M, Ona K, Dent T, Seifikar H, Hamilton EG & Fisher SJ 2017 Transcriptional dynamics of cultured human villous cytotrophoblasts. Endocrinology 158 1581–1594. (https://doi.org/10.1210/en.2016-1635)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rossi MN & Antonangeli F 2015 Cellular response upon stress: p57 contribution to the final outcome. Mediators of Inflammation 2015 259325. (https://doi.org/10.1155/2015/259325)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rouault C, Clement K, Guesnon M, Henegar C, Charles MA, Heude B, Evain-Brion D, Degrelle SA & Fournier T 2016 Transcriptomic signatures of villous cytotrophoblast and syncytiotrophoblast in term human placenta. Placenta 44 83–90. (https://doi.org/10.1016/j.placenta.2016.06.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sagrillo-Fagundes L, Assuncao Salustiano EM, Ruano R, Markus RP & Vaillancourt C 2018 Melatonin modulates autophagy and inflammation protecting human placental trophoblast from hypoxia/reoxygenation. Journal of Pineal Research 65 e12520. (https://doi.org/10.1111/jpi.12520)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Schneider JW, Gu W, Zhu L, Mahdavi V & Nadal-Ginard B 1994 Reversal of terminal differentiation mediated by p107 in Rb-/- muscle cells. Science 264 1467–1471. (https://doi.org/10.1126/science.8197461)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sherr CJ 1993 Mammalian G1 cyclins. Cell 73 1059–1065. (https://doi.org/10.1016/0092-8674(9390636-5)

  • Sherr CJ & Roberts JM 1999 CDK inhibitors: positive and negative regulators of G1-phase progression. Genes and Development 13 1501–1512. (https://doi.org/10.1101/gad.13.12.1501)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Stampone E, Caldarelli I, Zullo A, Bencivenga D, Mancini FP, Della Ragione F & Borriello A 2018 Genetic and epigenetic control of CDKN1C expression: importance in cell commitment and differentiation, tissue homeostasis and human diseases. International Journal of Molecular Sciences 19 1055. (https://doi.org/10.3390/ijms19041055)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Stewart MC, Kadlcek RM, Robbins PD, Macleod JN & Ballock RT 2004 Expression and activity of the CDK inhibitor p57Kip2 in chondrocytes undergoing hypertrophic differentiation. Journal of Bone and Mineral Research 19 123–132. (https://doi.org/10.1359/JBMR.0301209)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tarrade A, Lai Kuen R, Malassine A, Tricottet V, Blain P, Vidaud M & Evain-Brion D 2001 Characterization of human villous and extravillous trophoblasts isolated from first trimester placenta. Laboratory Investigation 81 1199–1211. (https://doi.org/10.1038/labinvest.3780334)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ullah Z, Kohn MJ, Yagi R, Vassilev LT & Depamphilis ML 2008 Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity. Genes and Development 22 3024–3036. (https://doi.org/10.1101/gad.1718108)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ullah Z, Lee CY & Depamphilis ML 2009 Cip/Kip cyclin-dependent protein kinase inhibitors and the road to polyploidy. Cell Division 4 10. (https://doi.org/10.1186/1747-1028-4-10)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Unek G, Ozmen A, Ozekinci M, Sakinci M & Korgun ET 2014 Immunolocalization of cell cycle proteins (p57, p27, cyclin D3, PCNA and Ki67) in intrauterine growth retardation (IUGR) and normal human term placentas. Acta histochemica 116 493–502. (https://doi.org/10.1016/j.acthis.2013.10.007)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wirt SE, Adler AS, Gebala V, Weimann JM, Schaffer BE, Saddic LA, Viatour P, Vogel H, Chang HY & Meissner A et al.2010 G1 arrest and differentiation can occur independently of Rb family function. Journal of Cell Biology 191 809–825. (https://doi.org/10.1083/jcb.201003048)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yabe S, Alexenko AP, Amita M, Yang Y, Schust DJ, Sadovsky Y, Ezashi T & Roberts RM 2016 Comparison of syncytiotrophoblast generated from human embryonic stem cells and from term placentas. PNAS 113 E2598–E2607. (https://doi.org/10.1073/pnas.1601630113)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang P, Liegeois NJ, Wong C, Finegold M, Hou H, Thompson JC, Silverman A, Harper JW, Depinho RA & Elledge SJ 1997 Altered cell differentiation and proliferation in mice lacking p57KIP2 indicates a role in Beckwith-Wiedemann syndrome. Nature 387 151–158. (https://doi.org/10.1038/387151a0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu L & Skoultchi AI 2001 Coordinating cell proliferation and differentiation. Current Opinion in Genetics and Development 11 91–97. (https://doi.org/10.1016/s0959-437x(0000162-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu X, Li HD, Xu Y, Guo L, Wu FX, Duan G & Wang J 2019 A hybrid clustering algorithm for identifying cell types from single-cell RNA-seq data. Genes 10 9 8. (https://doi.org/10.3390/genes10020098)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhu H, Peng B, Klausen C, Yi Y, Li Y, Xiong S, Von Dadelszen P & Leung PCK 2020 NPFF increases fusogenic proteins syncytin 1 and syncytin 2 via GCM1 in first trimester primary human cytotrophoblast cells. FASEB Journal 34 9419–9432. (https://doi.org/10.1096/fj.201902978R)

    • PubMed
    • Search Google Scholar
    • Export Citation