Extravillous trophoblast

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Extravillous trophoblasts(EVTs), are one form of differentiated trophoblast cells of the placenta. They are invasive mesenchymal cells which function to establish critical tissue connection in the developing placental-uterine interface. EVTs derive from progenitor cytotrophoblasts (CYTs), as does the other main trophoblast subtype, syncytiotrophoblast (SYN). They are sometimes called intermediate trophoblast. [1]

Contents

EVTs that derive from CYT cells on the surface of placental chorionic villi that come into contact with the uterine wall - at the placental bed - begin to express the HLA-G antigen. [2] Extravillous trophoblast (EVT) cells migrate from anchoring villi, and invade into the decidua basalis. Their main function is remodelling the uterine spiral arteries, to achieve an increase in the spiral artery diameter of from four to six times. This changes them from high-resistance low-flow vessels into large dilated vessels that provide good perfusion, and oxygenation to the developing placenta. When invasion is shallow it is inadequate, the arteries remain narrow at their openings into the intervillous space, and is the cause of pre-eclampsia, fetal growth restriction and still birth. [3] [4] [5]

EVT are a low-incidence (<5% of trophoblasts), but critical and multifunctional, subtype of trophoblast in the placenta.

Function

As the placenta forms and the cytotrophoblast layer grows and extends, distal villous CYT differentiate to cell column CYT which eventually detach and invade deeply to the maternal decidua as interstitial EVTs. [6] These EVTs anchor placental villi to the maternal decidua. Shallow implantation of EVT is associated with poor placentation and preeclampsia. Endovascular EVTs are also major regulators of oxygenation during early placental development. Initially, they plug maternal spiral arteries to maintain hypoxia and prevent blood perfusion. [7] [8] This protects the fetus and placenta from oxidative stress during early development in the histiotrophic (glandular nutrition) stage. As fetal nutrition switches to the hemotrophic (blood-derived nutrition) stage, EVT plugs dissolve and perfusion of maternal blood begins, allowing further development of both the fetus and placenta. [9] [5]

Formation

Cells that will eventually become extraembryonic placental trophoblasts are derived from the trophectoderm. As the trophectoderm separates from the inner cell mass during blastulation, early trophoblasts begin to form the placenta. [10] Later in placental development, both interstitial and endovascular EVTs form as underlying progenitor cell column CYTs undergo epithelial to mesenchymal transition (EMT). [11] This cellular process continually occurs as the CYT layer replenishes extravillous trophoblasts. EMT of CYT to EVT in the placenta is strongly controlled by the transcription factor T-cell factor 4 (TCF4) which is Wnt-dependent. [12] Canonical Wnt signaling pathways have many downstream development-related transcription factor gene targets, including TCF4. Since developing placental trophoblasts do not necessarily follow canonical EMT, it has been suggested that a placental trophoblast-specific hybrid EMT is a separate iteration. [11]

Biological markers

Placental trophoblast subtypes can be distinguished by certain markers that are exclusive to each subtype. Transition from epithelial CYT to mesenchymal EVT can be tracked by a loss of E-cadherin and gain of N-cadherin. EVTs can also be distinguished by expression of human leukocyte antigen G (HLA-G), which is not expressed by other placental trophoblasts. [13] As other trophoblast subtypes in the placental are epithelial, mesenchymal markers like vimentin and fibronectin can also be used for identification. These markers, however, are not specific to EVT and can also stain stromal cells in the placenta. [13] As trophoblasts develop, they express different integrins. Whereas CYT can be identified by ITGA6, EVTs strongly express ITGA5. [14] The existing in vitro EVT models detailed below recapitulate these markers and staining to varying degrees of accuracy.

In vitro models

As EVTs are a critical cellular subtype of the placenta and their dysfunction is associated with a myriad of gestational illnesses, [15] they are an attractive topic for research. Acquisition of this primary cell type from sensitive tissues can be difficult and inconsistent. First and second trimester placental tissue must usually be obtained from elective abortions, a designation requiring more NIH documentation and oversight. [16] Tissue from term placentas is more readily available but cannot be used to address questions related to early development and dynamics. Dissociation of trophoblasts from other cell types in placental tissue can be procedurally difficult and pure trophoblast subtype populations take great lengths to obtain. Then, the resulting primary trophoblast cells can then only be kept in culture for a few days. Thus, there is a high demand for accurate cell lines to model primary placental trophoblasts. The immortalized cell line HTR-8/SVneo is commonly used to model EVTs. Newer multipotent trophoblast stem cell systems can be induced to differentiate into HLA-G+ EVT from CYT. [13] Systems of placental organoids can also grow invasive EVT when cultured in Matrigel. [17] Each of these options varies in their utility and accuracy to primary EVTs. As research groups continue to develop better techniques of recapitulating primary cells in vitro, proper modeling of placental EVTs remains a goal of the field.

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The chorion is the outermost fetal membrane around the embryo in mammals, birds and reptiles (amniotes). It develops from an outer fold on the surface of the yolk sac, which lies outside the zona pellucida, known as the vitelline membrane in other animals. In insects it is developed by the follicle cells while the egg is in the ovary.

<span class="mw-page-title-main">Blastocyst</span> Structure formed around day 5 of mammalian embryonic development

The blastocyst is a structure formed in the early embryonic development of mammals. It possesses an inner cell mass (ICM) also known as the embryoblast which subsequently forms the embryo, and an outer layer of trophoblast cells called the trophectoderm. This layer surrounds the inner cell mass and a fluid-filled cavity known as the blastocoel. In the late blastocyst the trophectoderm is known as the trophoblast. The trophoblast gives rise to the chorion and amnion, the two fetal membranes that surround the embryo. The placenta derives from the embryonic chorion and the underlying uterine tissue of the mother. The name "blastocyst" arises from the Greek βλαστός blastos and κύστις kystis. In other animals this is a structure consisting of an undifferentiated ball of cells and is called a blastula.

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<span class="mw-page-title-main">Trophoblast</span> Early embryonic structure that gives rise to the placenta

The trophoblast is the outer layer of cells of the blastocyst. Trophoblasts are present four days after fertilization in humans. They provide nutrients to the embryo and develop into a large part of the placenta. They form during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg to become extraembryonic structures that do not directly contribute to the embryo. After blastulation, the trophoblast is contiguous with the ectoderm of the embryo and is referred to as the trophectoderm. After the first differentiation, the cells in the human embryo lose their totipotency because they can no longer form a trophoblast. They become pluripotent stem cells.

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<span class="mw-page-title-main">Syncytiotrophoblast</span> Embryonic cell of the placental surface

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  2. Increta – chorionic villi invaded into the myometrium.
  3. Percreta – chorionic villi invaded through the perimetrium.
<span class="mw-page-title-main">Cytotrophoblast</span>

"Cytotrophoblast" is the name given to both the inner layer of the trophoblast or the cells that live there. It is interior to the syncytiotrophoblast and external to the wall of the blastocyst in a developing embryo.

<span class="mw-page-title-main">Implantation (embryology)</span> First stage of pregnancy

Implantation (nidation) is the stage in the embryonic development of mammals in which the blastocyst hatches as the embryo, adheres, and invades into the wall of the female's uterus. Implantation is the first stage of gestation, and, when successful, the female is considered to be pregnant. In a woman, an implanted embryo is detected by the presence of increased levels of human chorionic gonadotropin (hCG) in a pregnancy test. The implanted embryo will receive oxygen and nutrients in order to grow.

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Raissa Nitabuch was a Russian pathologist who is known for her histological studies of the human placenta. The layer of fibrin that was thought to separate the uterine decidua from the fetoplacental trophoblast after birth was named the Nitabuch layer or Nitabuch membrane, thus becoming the only woman whose name is "affiliated with a macroscopic anatomical structure."

References

  1. ↑ Cierna, Z; Varga, I; Danihel L, Jr; Kuracinova, K; Janegova, A; Danihel, L (March 2016). "Intermediate trophoblast--A distinctive, unique and often unrecognized population of trophoblastic cells". Annals of Anatomy. 204: 45–50. doi:10.1016/j.aanat.2015.10.003. PMID   26581330.
  2. ↑ Moser, Gerit; Windsperger, Karin; Pollheimer, Jürgen; de Sousa Lopes, Susana Chuva; Huppertz, Berthold (1 October 2018). "Human trophoblast invasion: new and unexpected routes and functions". Histochemistry and Cell Biology. 150 (4): 361–370. doi:10.1007/s00418-018-1699-0. ISSN   1432-119X. PMC   6153604 . PMID   30046889.
  3. ↑ Abbas, Y; Turco, MY; Burton, GJ; Moffett, A (18 June 2020). "Investigation of human trophoblast invasion in vitro". Human Reproduction Update. 26 (4): 501–513. doi:10.1093/humupd/dmaa017. PMC   7473396 . PMID   32441309.
  4. ↑ Moser, Gerit; Weiss, Gregor; Sundl, Monika; Gauster, Martin; Siwetz, Monika; Lang-Olip, Ingrid; Huppertz, Berthold (1 March 2017). "Extravillous trophoblasts invade more than uterine arteries: evidence for the invasion of uterine veins". Histochemistry and Cell Biology. 147 (3): 353–366. doi:10.1007/s00418-016-1509-5. ISSN   1432-119X. PMC   5344955 . PMID   27774579.
  5. 1 2 Pollheimer, Jürgen; Vondra, Sigrid; Baltayeva, Jennet; Beristain, Alexander Guillermo; Knöfler, Martin (13 November 2018). "Regulation of Placental Extravillous Trophoblasts by the Maternal Uterine Environment". Frontiers in Immunology. 9: 2597. doi: 10.3389/fimmu.2018.02597 . ISSN   1664-3224. PMC   6243063 . PMID   30483261.
  6. ↑ Pijnenborg, R.; Bland, J.M.; Robertson, W.B.; Brosens, I. (October 1983). "Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy". Placenta. 4 (4): 397–413. doi:10.1016/S0143-4004(83)80043-5. PMID   6634666.
  7. ↑ Burton, Graham J.; Jauniaux, Eric; Charnock-Jones, D. Sephen (2010). "The influence of the intrauterine environment on human placental development". The International Journal of Developmental Biology. 54 (2–3): 303–312. doi: 10.1387/ijdb.082764gb . ISSN   0214-6282. PMID   19757391.
  8. ↑ Brosens, I.; Robertson, W. B.; Dixon, H. G. (April 1967). "The physiological response of the vessels of the placental bed to normal pregnancy". The Journal of Pathology and Bacteriology. 93 (2): 569–579. doi:10.1002/path.1700930218. ISSN   0368-3494. PMID   6054057.
  9. ↑ Pijnenborg, R.; Dixon, G.; Robertson, W.B.; Brosens, I. (January 1980). "Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy". Placenta. 1 (1): 3–19. doi:10.1016/S0143-4004(80)80012-9. PMID   7443635.
  10. ↑ Cockburn, Katie; Rossant, Janet (2010-04-01). "Making the blastocyst: lessons from the mouse". The Journal of Clinical Investigation. 120 (4): 995–1003. doi:10.1172/JCI41229. ISSN   0021-9738. PMC   2846056 . PMID   20364097.
  11. 1 2 DaSilva-Arnold, Sonia; James, Joanna L.; Al-Khan, Abdulla; Zamudio, Stacy; Illsley, Nicholas P. (December 2015). "Differentiation of first trimester cytotrophoblast to extravillous trophoblast involves an epithelial–mesenchymal transition". Placenta. 36 (12): 1412–1418. doi:10.1016/j.placenta.2015.10.013. PMID   26545962.
  12. ↑ Meinhardt, Gudrun; Haider, Sandra; Haslinger, Peter; Proestling, Katharina; Fiala, Christian; Pollheimer, Jürgen; Knöfler, Martin (2014-05-01). "Wnt-Dependent T-Cell Factor-4 Controls Human Etravillous Trophoblast Motility". Endocrinology. 155 (5): 1908–1920. doi: 10.1210/en.2013-2042 . ISSN   0013-7227. PMID   24605829.
  13. 1 2 3 Okae, Hiroaki; Toh, Hidehiro; Sato, Tetsuya; Hiura, Hitoshi; Takahashi, Sota; Shirane, Kenjiro; Kabayama, Yuka; Suyama, Mikita; Sasaki, Hiroyuki; Arima, Takahiro (2018-01-04). "Derivation of Human Trophoblast Stem Cells". Cell Stem Cell. 22 (1): 50–63.e6. doi: 10.1016/j.stem.2017.11.004 . ISSN   1875-9777. PMID   29249463.
  14. ↑ Knöfler, Martin; Haider, Sandra; Saleh, Leila; Pollheimer, Jürgen; Gamage, Teena K. J. B.; James, Joanna (2019). "Human placenta and trophoblast development: key molecular mechanisms and model systems". Cellular and Molecular Life Sciences. 76 (18): 3479–3496. doi:10.1007/s00018-019-03104-6. ISSN   1420-682X. PMC   6697717 . PMID   31049600.
  15. ↑ Khong, T. Y.; Wolf, F.; Robertson, W. B.; Brosens, I. (October 1986). "Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants". BJOG: An International Journal of Obstetrics and Gynaecology. 93 (10): 1049–1059. doi:10.1111/j.1471-0528.1986.tb07830.x. ISSN   1470-0328. PMID   3790464. S2CID   72967416.
  16. ↑ "4.1.14 Human Fetal Tissue Research". grants.nih.gov. Retrieved 2021-03-23.
  17. ↑ Turco, Margherita Y.; Gardner, Lucy; Kay, Richard G.; Hamilton, Russell S.; Prater, Malwina; Hollinshead, Michael; McWhinnie, Alasdair; Esposito, Laura; Fernando, Ridma; Skelton, Helen; Reimann, Frank (2019-04-26). "Trophoblast organoids as a model for maternal-fetal interactions during human placentation". Nature. 564 (7735): 263–267. doi:10.1038/s41586-018-0753-3. ISSN   0028-0836. PMC   7220805 . PMID   30487605.
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