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. 1997 Dec;151(6):1809–1818.

Human cytotrophoblast differentiation/invasion is abnormal in pre-eclampsia.

K H Lim 1, Y Zhou 1, M Janatpour 1, M McMaster 1, K Bass 1, S H Chun 1, S J Fisher 1
PMCID: PMC1858365  PMID: 9403732

Abstract

During human placental development, cytotrophoblast stem cells differentiate and invade the uterus. Simultaneously, the cells modulate their expression of several classes of stage-specific antigens that mark transitions in the differentiation process and play a role in either uterine invasion (integrin cell-extracellular matrix receptors and matrix metalloproteinase-9) or immune interactions (HLA-G). The pregnancy disease pre-eclampsia is associated with shallow cytotrophoblast invasion. Previously we showed, by immunofluorescence localization on placental tissue, that in pre-eclampsia invasive cytotrophoblasts fail to properly modulate their integrin repertoire. This finding suggests possible abnormalities in the differentiation pathway that leads to uterine invasion. Here we used a culture system that supports this differentiation process to compare the differentiative and invasive potential of cytotrophoblasts obtained from control (n = 8, 22 to 38 weeks) and pre-eclamptic (n = 9, 24 to 38 weeks) placentas. In culture, the cells from pre-eclamptic placentas failed to properly modulate alpha1 integrin and matrix metalloproteinase-9 expression at the protein and mRNA levels. Their invasive potential was also greatly reduced. Likewise, the cells failed to up-regulate HLA-G protein and mRNA expression. These results suggest that defective cytotrophoblast differentiation/invasion can have significant consequences to the outcome of human pregnancy (ie, development of pre-eclampsia) and that, by the time delivery becomes necessary, the defect is not reversed by removing the cells from the maternal environment.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bass K. E., Morrish D., Roth I., Bhardwaj D., Taylor R., Zhou Y., Fisher S. J. Human cytotrophoblast invasion is up-regulated by epidermal growth factor: evidence that paracrine factors modify this process. Dev Biol. 1994 Aug;164(2):550–561. doi: 10.1006/dbio.1994.1223. [DOI] [PubMed] [Google Scholar]
  2. Berg C. J., Atrash H. K., Koonin L. M., Tucker M. Pregnancy-related mortality in the United States, 1987-1990. Obstet Gynecol. 1996 Aug;88(2):161–167. doi: 10.1016/0029-7844(96)00135-4. [DOI] [PubMed] [Google Scholar]
  3. Brosens I. A., Robertson W. B., Dixon H. G. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu. 1972;1:177–191. [PubMed] [Google Scholar]
  4. Brosens I., Robertson W. B., Dixon H. G. The physiological response of the vessels of the placental bed to normal pregnancy. J Pathol Bacteriol. 1967 Apr;93(2):569–579. doi: 10.1002/path.1700930218. [DOI] [PubMed] [Google Scholar]
  5. Chesley L. C. Diagnosis of preeclampsia. Obstet Gynecol. 1985 Mar;65(3):423–425. [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Chumbley G., King A., Robertson K., Holmes N., Loke Y. W. Resistance of HLA-G and HLA-A2 transfectants to lysis by decidual NK cells. Cell Immunol. 1994 May;155(2):312–322. doi: 10.1006/cimm.1994.1125. [DOI] [PubMed] [Google Scholar]
  8. Cross J. C., Flannery M. L., Blanar M. A., Steingrimsson E., Jenkins N. A., Copeland N. G., Rutter W. J., Werb Z. Hxt encodes a basic helix-loop-helix transcription factor that regulates trophoblast cell development. Development. 1995 Aug;121(8):2513–2523. doi: 10.1242/dev.121.8.2513. [DOI] [PubMed] [Google Scholar]
  9. Damsky C. H., Fitzgerald M. L., Fisher S. J. Distribution patterns of extracellular matrix components and adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the invasive pathway, in vivo. J Clin Invest. 1992 Jan;89(1):210–222. doi: 10.1172/JCI115565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Damsky C. H., Librach C., Lim K. H., Fitzgerald M. L., McMaster M. T., Janatpour M., Zhou Y., Logan S. K., Fisher S. J. Integrin switching regulates normal trophoblast invasion. Development. 1994 Dec;120(12):3657–3666. doi: 10.1242/dev.120.12.3657. [DOI] [PubMed] [Google Scholar]
  11. De S. K., McMaster M. T., Andrews G. K. Endotoxin induction of murine metallothionein gene expression. J Biol Chem. 1990 Sep 5;265(25):15267–15274. [PubMed] [Google Scholar]
  12. Deniz G., Christmas S. E., Brew R., Johnson P. M. Phenotypic and functional cellular differences between human CD3- decidual and peripheral blood leukocytes. J Immunol. 1994 May 1;152(9):4255–4261. [PubMed] [Google Scholar]
  13. Fisher S. J., Cui T. Y., Zhang L., Hartman L., Grahl K., Zhang G. Y., Tarpey J., Damsky C. H. Adhesive and degradative properties of human placental cytotrophoblast cells in vitro. J Cell Biol. 1989 Aug;109(2):891–902. doi: 10.1083/jcb.109.2.891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Genbacev O., Joslin R., Damsky C. H., Polliotti B. M., Fisher S. J. Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. J Clin Invest. 1996 Jan 15;97(2):540–550. doi: 10.1172/JCI118447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gerretsen G., Huisjes H. J., Elema J. D. Morphological changes of the spiral arteries in the placental bed in relation to pre-eclampsia and fetal growth retardation. Br J Obstet Gynaecol. 1981 Sep;88(9):876–881. doi: 10.1111/j.1471-0528.1981.tb02222.x. [DOI] [PubMed] [Google Scholar]
  16. Guillemot F., Nagy A., Auerbach A., Rossant J., Joyner A. L. Essential role of Mash-2 in extraembryonic development. Nature. 1994 Sep 22;371(6495):333–336. doi: 10.1038/371333a0. [DOI] [PubMed] [Google Scholar]
  17. Khong T. Y., De Wolf F., Robertson W. B., Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol. 1986 Oct;93(10):1049–1059. doi: 10.1111/j.1471-0528.1986.tb07830.x. [DOI] [PubMed] [Google Scholar]
  18. Kovats S., Main E. K., Librach C., Stubblebine M., Fisher S. J., DeMars R. A class I antigen, HLA-G, expressed in human trophoblasts. Science. 1990 Apr 13;248(4952):220–223. doi: 10.1126/science.2326636. [DOI] [PubMed] [Google Scholar]
  19. Kurman R. J., Main C. S., Chen H. C. Intermediate trophoblast: a distinctive form of trophoblast with specific morphological, biochemical and functional features. Placenta. 1984 Jul-Aug;5(4):349–369. doi: 10.1016/s0143-4004(84)80015-6. [DOI] [PubMed] [Google Scholar]
  20. Lehrach H., Diamond D., Wozney J. M., Boedtker H. RNA molecular weight determinations by gel electrophoresis under denaturing conditions, a critical reexamination. Biochemistry. 1977 Oct 18;16(21):4743–4751. doi: 10.1021/bi00640a033. [DOI] [PubMed] [Google Scholar]
  21. Librach C. L., Feigenbaum S. L., Bass K. E., Cui T. Y., Verastas N., Sadovsky Y., Quigley J. P., French D. L., Fisher S. J. Interleukin-1 beta regulates human cytotrophoblast metalloproteinase activity and invasion in vitro. J Biol Chem. 1994 Jun 24;269(25):17125–17131. [PubMed] [Google Scholar]
  22. Librach C. L., Werb Z., Fitzgerald M. L., Chiu K., Corwin N. M., Esteves R. A., Grobelny D., Galardy R., Damsky C. H., Fisher S. J. 92-kD type IV collagenase mediates invasion of human cytotrophoblasts. J Cell Biol. 1991 Apr;113(2):437–449. doi: 10.1083/jcb.113.2.437. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. McMaster M. T., Librach C. L., Zhou Y., Lim K. H., Janatpour M. J., DeMars R., Kovats S., Damsky C., Fisher S. J. Human placental HLA-G expression is restricted to differentiated cytotrophoblasts. J Immunol. 1995 Apr 15;154(8):3771–3778. [PubMed] [Google Scholar]
  24. Ramos-DeSimone N., Moll U. M., Quigley J. P., French D. L. Inhibition of matrix metalloproteinase 9 activation by a specific monoclonal antibody. Hybridoma. 1993 Aug;12(4):349–363. doi: 10.1089/hyb.1993.12.349. [DOI] [PubMed] [Google Scholar]
  25. Redline R. W., Patterson P. Pre-eclampsia is associated with an excess of proliferative immature intermediate trophoblast. Hum Pathol. 1995 Jun;26(6):594–600. doi: 10.1016/0046-8177(95)90162-0. [DOI] [PubMed] [Google Scholar]
  26. Robertson W. B., Brosens I. A., Dixon H. G. Placental bed vessels. Am J Obstet Gynecol. 1973 Sep 15;117(2):294–295. doi: 10.1016/0002-9378(73)90655-8. [DOI] [PubMed] [Google Scholar]
  27. Sibai B. M. The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing? Am J Obstet Gynecol. 1990 Feb;162(2):311–316. doi: 10.1016/0002-9378(90)90376-i. [DOI] [PubMed] [Google Scholar]
  28. Wilhelm S. M., Collier I. E., Marmer B. L., Eisen A. Z., Grant G. A., Goldberg G. I. SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J Biol Chem. 1989 Oct 15;264(29):17213–17221. [PubMed] [Google Scholar]
  29. Zhou Y., Damsky C. H., Chiu K., Roberts J. M., Fisher S. J. Preeclampsia is associated with abnormal expression of adhesion molecules by invasive cytotrophoblasts. J Clin Invest. 1993 Mar;91(3):950–960. doi: 10.1172/JCI116316. [DOI] [PMC free article] [PubMed] [Google Scholar]

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