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Morphological changes of placental syncytium and their implications for the pathogenesis of preeclampsia

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Abstract

Preeclampsia is a hypertensive disease that complicates many pregnancies, typically presenting with new-onset or worsening hypertension and proteinuria. It is well recognized that the placental syncytium plays a key role in the pathogenesis of preeclampsia. This review summarizes the findings pertaining to the structural alterations in the syncytium of preeclamptic placentas and analyzes their pathological implications for the development of preeclampsia. Changes in the trophoblastic lineage, including those in the proliferation of cytotrophoblasts, the formation of syncytiotrophoblast through cell fusion, cell apoptosis and syncytial deportation, are discussed in the context of preeclampsia. Extensive correlations are made between functional deficiencies and the alterations on the levels of gross anatomy, tissue histology, cellular events, ultrastructure, molecular pathways, and gene expression. Attention is given to the significance of dynamic changes in the syncytial turnover in preeclamptic placentas. Specifically, experimental evidences for the complex and obligatory role of syncytin-1 in cell fusion, cell-cycle regulation at the G1/S transition, and apoptosis through AIF-mediated pathway, are discussed in detail in the context of syncytium homeostasis. Finally, the recent observations on the aberrant fibrin deposition in the trophoblastic layer and the trophoblast immature phenotype in preeclamptic placentas and their potential pathogenic impact are also reviewed.

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References

  1. Hypertension in Pregnancy (2013) Task force on hypertension in pregnancy. American College of Obstetricians and Gynecologists. http://www.acog.org/-/media/Task-Force-and-Work-Group-Reports/HypertensioninPregnancy.pdf?dmc=1. Accessed Jan 2015

  2. Beck S, Wojdyla D, Say L, Betran AP, Merialdi M, Requejo JH, Rubens C, Menon R, Van Look PFA (2009) The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ 88:31–38

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mercuro G, Bassareo PP, Flore G, Fanos V, Dentamaro I, Scicchitano P, Laforgia N, Ciccone MM (2013) Prematurity and low weight at birth as new conditions predisposing to an increased cardiovascular risk. Eur J Prev Cardiol 20(2):357–367

    Article  PubMed  Google Scholar 

  4. Moster D, Lie RT, Markstad T (2008) Long-term medical and social consequences of preterm birth. N Engl J Med 359(3):262–273

    Article  PubMed  CAS  Google Scholar 

  5. Enguobahrie D, Abetwe D, Sorensen T, Willoughby D, Chidambaram K, Williams M (2011) Placental microRNA expression in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 204:178.2–178.21

    Google Scholar 

  6. Gauster M, Moser G, Orendi K, Huppertz B (2009) Factors involved in regulating trophoblast fusion: potential role in the development of preeclampsia. Placenta 23:49–54

    Article  CAS  Google Scholar 

  7. Redman CWG, Sargent IL (2008) Circulating microparticles in normal pregnancy and pre-eclampsia. Placenta 29:73–77

    Article  Google Scholar 

  8. Gauster M, Huppertz B (2008) Fusion of cytotrophoblast with syncytiotrophoblast in the human placenta: factors involved in syncytialization. J Reprod Med Endocrinol 5:76–82

    CAS  Google Scholar 

  9. Dokras A, Hoffmann D, Eaastvold J, Kienzle M, Gruman L, Kirby P, Weiss R, Davisson R (2006) Severe feto-placental abnormalities precede the onset of hypertension and proteinuria in a mouse model of preeclampsia. Biol Reprod 75(6):899–907

    Article  PubMed  CAS  Google Scholar 

  10. Cross J (2000) Genetic insights into trophoblast differentiation and placental morphogenesis. Semin Cell Dev Biol 11(2):105–113

    Article  PubMed  CAS  Google Scholar 

  11. Newhouse S, Davidge S, Winkler-Lowen B, Demianczuk N, Guklbert L (2007) In vitro differentiation of villous trophoblasts from pregnancies complicated by intrauterine growth restriction with and without preeclampsia. Placenta 28(10):999–1003

    Article  PubMed  CAS  Google Scholar 

  12. Brouillet S, Hoffmann P, Feige JJ, Alfaidy N (2012) EG-VEGF: a key endocrine factor in placental development. Trends Endocrinol Metab 23(10):501–508

    Article  PubMed  CAS  Google Scholar 

  13. Maynard SE, Karumanchi SA (2011) Angiogenic factors and preeclampsia. Semin Nephrol 31(1):33–46

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Stepan H, Unversucht A, Wessel N, Faber R (2007) Predictive value of maternal angiogenic factors in second trimester pregnancies with abnormal uterine perfusion. Hypertension 49(4):818–824

    Article  PubMed  CAS  Google Scholar 

  15. Mayhew TM (2014) Turnover of human villous trophoblast in normal pregnancy: what do we know and what do we need to know? Placenta 35(4):229–240

    Article  PubMed  CAS  Google Scholar 

  16. Huang Q, Li J, Wang F, Oliver MT, Tipton T, Gao Y, Jiang SW (2013) Syncytin-1 modulates placental trophoblast cell proliferation by promoting G1/S transition. Cell Signal 25(4):1027–1035

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Mayhew TM, Manwani R, Ohadike C, Wijeskara J, Baker PN (2007) The placenta in pre-eclampsia and intrauterine growth restriction: studies on exchange surface areas, diffusion distances and villous membrane diffusive conductances. Placenta 28(2–3):233–238

    Article  PubMed  CAS  Google Scholar 

  18. Redline RW, Patterson P (1995) Pre-eclampsia is associated with an excess of proliferative immature intermediate trophoblast. Hum Pathol 26(6):594–600

    Article  PubMed  CAS  Google Scholar 

  19. Vatgas A, Toufaily C, LeBellego F, Rassart E, Lafond J, Barbeau B (2011) Reduced expression of both syncytin 1 and syncytin 2 correlates with severity of preeclampsia. Reprod Sci 18(11):1085–1091

    Article  Google Scholar 

  20. Ruebner M, Strissel PL, Ekici AB, Stiegler E, Dammer U, Goecke TW, Faschingbauer F, Fahlbusch FB, Beckmann MW, Strick R (2013) Reduced syncytin-1 expression levels in placental syndromes correlates with epigenetic hypermethylation of the ERVW-1 promotor region. PLoS One 8:e56145

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Zhuang XW, Li J, Brost BC, Xia XY, Chen HB, Wang CX, Jiang SW (2014) Decreased expression and altered methylation of syncytin-1 gene in human placentas associated with preeclampsia. Curr Pharm Des 20(11):1796–1802

    Article  PubMed  CAS  Google Scholar 

  22. Gao Y, He Z, Wang Z, Luo Y, Sun H, Zhou Y, Huang L, Li M, Fang Q, Jiang S (2012) Increased expression and altered methylation of HERVWE1 in the human placentas of smaller fetuses from monozygotic, dichorionic, discordant twins. PLoS One 7:e33503

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Gong JS, Kim GJ (2014) The role of autophagy in the placenta as a regulator of cell death. Clin Exp Reprod Med 41(3):97–107

    Article  PubMed  PubMed Central  Google Scholar 

  24. Oh SY, Choi SJ, Kim KH, Cho EY, Kim JH, Roh CR (2008) Autophagy-related proteins, LC3 and Beclin-1, in placentas from pregnancies complicated by preeclampsia. Reprod Sci 15(9):912–920

    Article  PubMed  CAS  Google Scholar 

  25. Hung TH, Chen SF, Lo LM, Li MJ, Yeh YL, Hsieh TT (2012) Increased autophagy in placentas of intrauterine growth-restricted pregnancies. PLoS One 7:e40957

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Chen B, Longtine SM, Nelson DM (2012) Hypoxia induces autophagy in primary human trophoblasts. Endocrinology 153(10):4946–4954

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Cha HH, Hwang JR, Kim HY, Choi SJ, Oh SY, Roh CR (2014) Autophagy induced by tumor necrosis factor a mediates intrinsic apoptosis in trophoblastic cells. Reprod Sci 21(5):612–622

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Asklund K, Chamley L (2011) Trophoblast deportation part I: review of the evidence demonstrating trophoblast shedding and deportation during human pregnancy. Placenta 32(10):716–723

    Article  Google Scholar 

  29. Douglas GW, Thomas L, Carr M, Cullen NM, Morris R (1959) Trophoblast in the circulating blood during pregnancy. Am J Obstet Gynecol 78:960–973

    PubMed  CAS  Google Scholar 

  30. Schmidt M, Hoffman B, Beelen D, Gellhaus A, Winterhager E, Kimming R (2008) Detection of circulating trophoblast particles in peripheral maternal blood in preeclampsia complicated pregnancies. Hypertens Pregnancy 27(2):131–142

    Article  PubMed  Google Scholar 

  31. Heazell AE, Moll SJ, Jones CJ, Baker PN, Crocker IP (2007) Formation of syncytial knots is increased by hyperoxia, hypoxia and reactive oxygen species. Placenta 28:33–40

    Article  Google Scholar 

  32. Austgulen R, Isaksen C, Chedwick L, Romundstad P, Vatten L, Craven C (2004) Preeclampsia: associated with increased syncytial apoptosis when the infant is small-for-gestational-age. J Reprod Immunol 61(1):39–50

    Article  PubMed  Google Scholar 

  33. Rajakumar A, Cerdeira AS, Rana S, Zsengeller Z, Edmunds L, Jeyabalan A, Hubel CA, Stillman IE, Parikh SM, Karumanchi SA (2012) Transcriptionally active syncytial aggregates in the maternal circulation may contribute to circulating soluble fms-like tyrosine kinase 1 in preeclampsia. Hypertension 59(2):256–264

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Chamley LW, Chen Q, Ding J, Stone PR, Abumaree M (2011) Trophoblast deportation: just a waste disposal system or antigen sharing? J Reprod Immunol 88(2):99–105

    Article  PubMed  CAS  Google Scholar 

  35. Pantham P, Askelund KJ, Chamley LW (2011) Trophoblast deportation part II: a review of the maternal consequences of trophoblast deportation. Placenta 32(10):724–731

    Article  PubMed  CAS  Google Scholar 

  36. Huppertz B (2010) IFPA award in placentology lecture: biology of the placental syncytiotrophoblast—myths and facts. Placenta 31:75–81

    Article  Google Scholar 

  37. Lockwood CJ, Huang SJ, Krikun G, Caze R, Rahman M, Buchwalder LF, Schatz F (2011) Decidual hemostasis, inflammation and angiogenesis in pre-eclampsia. Semin Thromb Hemost 37(2):158–164

    Article  PubMed  CAS  Google Scholar 

  38. Staff AC, Johnsen GM, Dechend R, Redman CW (2014) Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors. J Reprod Immunol 101–102:120–126

    Article  PubMed  Google Scholar 

  39. Burton GJ, Jones CJ (2009) Syncytial knots, sprouts, apoptosis, and trophoblast deportation from the human placenta. Taiwan J Obstet Gynecol 48(1):28–37

    Article  PubMed  Google Scholar 

  40. Loukeris K, Sela R, Baergen RN (2010) Syncytial knots as a reflection of placental maturity: reference values for 20 to 40 weeks’ gestational age. Pediatr Dev Pathol 13(4):305–309

    Article  PubMed  Google Scholar 

  41. Benirschke K (1998) Remarkable placenta. Clin Anat 11(3):194–205

    Article  PubMed  CAS  Google Scholar 

  42. Fogarty NM, Ferguson-Smith AC, Burton GJ (2013) Syncytial knots (Tenney–Parker changes) in the human placenta: evidence of loss of transcriptional activity and oxidative damage. Am J Pathol 183(1):144–152

    Article  PubMed  Google Scholar 

  43. Stark M, Clark L, Craver R (2014) Histologic differences in placentas of preeclamptic/eclamptic gestations by birthweight, placental weight, and time of onset. Pediatr Dev Pathol 17(3):181–189

    Article  PubMed  Google Scholar 

  44. Devisme L, Merlot B, Ego A, Houfflin-Debarge V, Deruelle P, Subtil D (2013) A case–control study of placental lesions associated with pre-eclampsia. Int J Gynaecol Obstet 120(2):165–168

    Article  PubMed  Google Scholar 

  45. Salgado S, Salgado M (2011) Structural changes in pre-eclamptic and eclamptic placentas—an ultrastructural study. J Coll Physicians Surg Pak 21(8):482–486

    PubMed  Google Scholar 

  46. Coleman SJ, Gerza L, Jones CJ, Sibley CP, Aplin JD, Heazell AE (2013) Syncytial nuclear aggregates in normal placenta show increased nuclear condensation, but apoptosis and cytoskeletal redistribution are uncommon. Placenta 34(5):449–455

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Huang Q, Chen H, Wang F, Brost BC, Li J, Gao Y, Li Z, Gao Y, Jiang SW (2014) Reduced syncytin-1 expression in choriocarcinoma BeWo cells activates the calpain1-AIF-mediated apoptosis, implication for preeclampsia. Cell Mol Life Sci 71(16):3151–3165

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Hwang HS, Sohn IS, Kwon HS (2012) The clinical significance of large placental lakes. Eur J Obstet Gynecol Reprod Biol 162(2):139–143

    Article  PubMed  Google Scholar 

  49. Petersen OMF, Heller D, Joshi V (2006) Handbook of placental pathology. Taylor & Francis, Oxford

    Google Scholar 

  50. Hung TH, Skepper JN, Charnock-Jones DS, Burton GJ (2002) Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circ Res 90(12):1274–1281

    Article  PubMed  CAS  Google Scholar 

  51. Guller S (2009) Role of the syncytium in placenta-mediated complications of preeclampsia. Thromb Res 124(4):389–392

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. Narasimah A, Vasudeva DS (2011) Spectrum of changes in placenta in toxemia of pregnancy. Indian J Pathol Microbiol 54(1):15–20

    Article  Google Scholar 

  53. Hladunewich M, Karumanchi SA, Lafayette R (2007) Pathophysiology of the clinical manifestations of preeclampsia. Clin J Am Soc Nephrol 2(3):543–549

    Article  PubMed  Google Scholar 

  54. Khong TY, De Wolf F, Robertson WB, Brosens I (1986) Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol 93(10):1049–1059

    Article  PubMed  CAS  Google Scholar 

  55. Tenney B, Parker F (1940) The placenta in toxemia of pregnancy. Am J Obstet Gynecol 39(6):1000–1005

    Google Scholar 

  56. Sankar KD, Bhanu PS, Kiran S, Ramakrishna BA, Shanthi V (2012) Vasculosyncytial membrane in relation to syncytial knots complicates the placenta in preeclampsia: a histomorphometrical study. Anat Cell Biol 45(2):86–91

    Article  PubMed  PubMed Central  Google Scholar 

  57. Sodhi S, Mohan H, Jaiswal TS, Mohan PS, Rathee S (1990) Placental pathology in preeclampsia eclampsia syndrome. Indian J Pathol Microbiol 33(1):11–16

    PubMed  CAS  Google Scholar 

  58. Soma H, Yoshida K, Mukaida T, Tabuchi Y (1982) Morphologic changes in the hypertensive placenta. Contrib Gynecol Obstet 9:58–75

    PubMed  CAS  Google Scholar 

  59. Ishihara N, Matsuo H, Murakoshi H, Laoag-Fernandez JB, Samoto T, Mauruo T (2002) Increased apoptosis in the syncytiotrophoblast in human term placentas complicated by either preeclampsia or intrauterine growth retardation. Am J Obstet Gyncecol 186(1):158–166

    Article  Google Scholar 

  60. Jones CJ, Fox H (1980) An ultrastructural and ultrahistochemical study of the human placenta in maternal pre-eclampsia. Placenta 1(1):61–76

    Article  PubMed  CAS  Google Scholar 

  61. MacLennan AH, Sharp F, Shaw-Dunn J (1972) The ultrastructure of human trophoblast in spontaneous and induced hypoxia using a system of organ culture. J Obstet Gynaecol Br Commonw 79(2):113–121

    Article  Google Scholar 

  62. Huang Q, Chen H, Li J, Oliver M, Ma X, Byck D, Gao Y, Jiang S (2013) Epigenetic and non-epigenetic regulation of syncytin-1 expression in human placenta and carrier tissues. Cell Signal 26(3):648–656

    Article  PubMed  CAS  Google Scholar 

  63. Langbein M, Strick R, Strissel PL, Vogt N, Parsch H, Beckman MW, Schild RL (2008) Impaired cytotrophoblast cell–cell fusion is associated with reduced syncytin and increased apoptosis in patients with placental dysfunction. Mol Reprod Dev 75(1):175–183

    Article  PubMed  Google Scholar 

  64. Matouskova M, Blazkova J, Pajer P, Pavlicek A, Hejnar J (2006) CpG methylation suppresses transcriptional activity of human syncytin-1 in non-placental tissues. Exp Cell Res 312(7):1011–1020

    Article  PubMed  CAS  Google Scholar 

  65. Lee X, Keith JC Jr, Stumm N, Moutsatsos I, McCoy JM, Crum CP, Genest D, Chin D, Ehrenfels C, Pijnenborg R, van Assche FA, Mi S (2001) Downregulation of placental syncytin expression and abnormal protein localization in pre-eclampsia. Placenta 22(10):808–812

    Article  PubMed  CAS  Google Scholar 

  66. Arnholdt H, Meisel F, Fandrey K, Lohrs U (1991) Proliferation of villous trophoblast of the human placenta in normal and abnormal pregnancies. Virch Arch B Cell Pathol Incl Mol Pathol 60(6):365–372

    Article  CAS  Google Scholar 

  67. Knerr I, Weigel C, Linnemann K, Dötsch J, Meissner U, Fusch C, Rascher W (2003) Transcriptional effects of hypoxia on fusiogenic syncytin and its receptor ASCT2 in human cytotrophoblast BeWo cells and in ex vivo perfused placental cotyledons. Am J Obstet Gynecol 189(2):583–588

    Article  PubMed  CAS  Google Scholar 

  68. Tolosa JM, Schjenken JE, Clifton VL, Vargas A, Barbeau B, Lowry P, Maiti K, Smith R (2012) The endogenous retroviral envelope protein syncytin-1 inhibits LPS/PHA-stimulated cytokine responses in human blood and is sorted into placental exosomes. Placenta 33(11):933–941

    Article  PubMed  CAS  Google Scholar 

  69. Gilabert J, Estellés A, Grancha S, España F, Aznar J (1995) Fibrinolytic system and reproductive process with special reference to fibrinolytic failure in pre-eclampsia. Hum Reprod 10:121–131

    Article  PubMed  CAS  Google Scholar 

  70. Kanfer A, Bruch JF, Nguyen G, He CJ, Delarue F, Flahault A, Nessmann C, Uzan S (1996) Increased placental antifibrinolytic potential and fibrin deposits in pregnancy-induced hypertension and preeclampsia. Lab Invest 74(1):253–258

    PubMed  CAS  Google Scholar 

  71. Tanjung MT, Siddik HD, Hariman H, Koh SC (2005) Coagulation and fibrinolysis in preeclampsia and neonates. Clin Appl Thromob Hemost 11(4):467–473

    Article  CAS  Google Scholar 

  72. Pinheiro MB, Gomes KB, Dusse LM (2013) Fibrinolytic system in preeclampsia. Clin Chim Acta 416:67–71

    Article  PubMed  CAS  Google Scholar 

  73. Guller S, Yula YM, Han-Hsuan F, Krikun G, Abrahams VM, Mor G (2008) The placental syncytium and the pathophysiology of preeclampsia and intrauterine growth restriction: a novel assay to assess syncytial protein expression. Ann N Y Acad Sci 1127:129–133

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  74. Arkwright PD, Rademacher TW, Dwek RA, Redman CW (1993) Preeclampsia is associated with an increase in trophoblast glycogen content and glycogen synthase activity, similar to that found in hydatidiform moles. J Clin Investig 91(6):2744–2753

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  75. Salge AK, Rocha KM, Xavier RM, Ramalho WS, Rocha ÉL, Guimarães JV, Silva RC, Siqueira KM, Abdalla DR, Michelin MA, Murta EF (2012) Macroscopic placental changes associated with fetal and maternal events in diabetes mellitus. Clinics (Sao Paulo) 67(10):1203–1208

    Article  Google Scholar 

  76. Nahar L, Nahar K, Hossain MI, Yasmin H, Annur BM (2015) Placental changes in pregnancy induced hypertension and its impacts on fetal outcome. Mymensingh Med J 24(1):9–17

    PubMed  CAS  Google Scholar 

  77. Chen KH, Chen LR, Lee YH (2011) Exploring the relationship between preterm placental calcification and adverse maternal and fetal outcome. Ultrasound Obstet Gynecol 37(3):328–334

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Georgia Research Alliance (GRA) Distinguished Scholarship (S.-W. Jiang); NIH R01 HD41577 (S.-W. Jiang); The Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents (X. Zhu); Seed Funds of Mercer University School of Medicine (S.-W. Jiang, J. Li).

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Correspondence to Xueqiong Zhu or Shi-Wen Jiang.

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C. S. Roland, J. Hu, C.-E. Ren, H. Chen contributed equally to this work.

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Roland, C.S., Hu, J., Ren, CE. et al. Morphological changes of placental syncytium and their implications for the pathogenesis of preeclampsia. Cell. Mol. Life Sci. 73, 365–376 (2016). https://doi.org/10.1007/s00018-015-2069-x

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