This page introduces an overview of aspects of the basic fetal subunit of the placenta, the placental villi development. In early placentation, each villi proceeds through a similar initial program of development. In later placentation, villi morphologically differentiate into a limited range of villi functional changes reflecting their specialization. The major initial contribution is from the trophoblast shell that surrounds the conceptus and later by the development of extraembryonic mesoderm and blood vessel differentiation. There are three main types of trophoblast cells that differentiate:
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Page Links: Introduction | Recent Findings | Cytotrophoblast Layer | Syncytiotrophoblast Layer | Mesenchymal Villi | Villi Trimester Development | Extravillous Trophoblast Outgrowth | Placenta Vascular Organisation | Molecular | Terms | Glossary |References | About Notes
Related Pages: Placenta Introduction | Maternal Decidua | Placental Abnormalities | Stage 13/14 | Stage22 | Placental Histology | Placental Vascular Beds | Blood | Blood Vessels | Birth | Stem Cells - Cord Blood
There is a new interpretation of the changes that are occuring in the cytotrophoblast (CTB) layer during early to full-term human placenta development. Traditionally the interpretation was that the cytotrophoblast layer thinned and became discontinuous towards term. The thinning is thought due to the epithelium surface expanding at a faster rate than its volume. Two recent studies suggest that while the cytotrophoblast layer does indeed thin, it does not become discontinuous.
Cytotrophoblast cells (CTB) are connected to each other laterally and to the overlying syncytium by mainly desmosomal junctions.
Jones CJ, Harris LK, Whittingham J, Aplin JD, Mayhew TM. A re-appraisal of the morphophenotype and basal lamina coverage of cytotrophoblasts in human term placenta. Placenta. 2008 Feb;29(2):215-9. Epub 2007 Dec 20. PMID: 18082881
"We conclude that CT cells transform from a cuboidal phenotype early in gestation to flattened cells with multiple interconnecting processes. The CT layer thins but maintains a functional network within which cells intercommunicate without compromising substance transfer via the syncytium."
Mori M, Ishikawa G, Luo SS, Mishima T, Goto T, Robinson JM, Matsubara S, Takeshita T, Kataoka H, Takizawa T. The cytotrophoblast layer of human chorionic villi becomes thinner but maintains its structural integrity during gestation. Biol Reprod. 2007 Jan;76(1):164-72. Epub 2006 Oct 11.
PMID: 17035639
"According to the embryology and placentology literature, during the first trimester, the cytotrophoblast (CTB) layer that is subjacent to the syncytiotrophoblast (STB) and supported by a basal lamina is nearly complete, but later, it becomes discontinuous. ...In full-term placenta, the cell surface of the CTB layer was spread over the basal lamina but was not interrupted. Morphometric analysis showed that throughout the villous tree, 80% of the continuity of the CTB layer of full-term placenta and 90% of that of first-trimester placenta were preserved. Gestation was accompanied by unique structural change in the basal domain of the trophoblast layer. The initially cuboidal-shaped CTB cells were transformed to flat cells with many cellular processes that, together with those of the adjacent STB, eventually covered the trophoblast basal lamina in a complex network of interdigitations." (More? Villi Development)
Villous Cytotrophoblast Marker - Hepatocyte growth factor activator inhibitor 1 (HAI-1) a membrane antigen.
Extravillous Trophoblast Marker - HLA class I, some CD105 positive, EBV-induced gene 3 (EBI3)
Syncytiotrophoblast Marker - CD105, EBV-induced gene 3 (EBI3), p28 a heterodimeric cytokine (PMID: 17659773) (PMID: 12657516)
Mucin 15 - (MUC15) protein was expressed by both cytotrophoblasts and syncytiotrophoblasts (PMID: 17720698)
"initially cuboidal-shaped CTB cells were transformed to flat cells with many cellular processes that, together with those of the adjacent STB, eventually covered the trophoblast basal lamina in a complex network of interdigitations."
Mori M, Ishikawa G, Luo SS, Mishima T, Goto T, Robinson JM, Matsubara S, Takeshita T, Kataoka H, Takizawa T. [See Related Articles] The cytotrophoblast layer of human chorionic villi becomes thinner but maintains its structural integrity during gestation. Biol Reprod. 2007 Jan;76(1):164-72.
The syncytiotrophoblast (STB) layer forms the epithelial covering of the entire villous tree. These cells are multinucleated, terminally-differentiated syncytium formed by the fusion of the underlying progenitor cytotrophoblast (CTB) cells. The process is described as "syncytialization" and is mediated by syncytin-1, an envelope protein of a human endogenous retrovirus W (HERV-W). The differentiation is regulated by chorionic gonadotropin (hCG) and the fusion of cytotrophoblast cells is ongoing during placental development.
Cellular parts derived from the syncytiotrophoblasts (apoptotic nuclei and microparticulate debris) can be shed into the maternal blood in which they are bathed. The apototic process appears to be part of the fusion mechanism between cytotrophoblast and the overlying multinucleate syncytiotrophoblast layer.
Studies have suggested that these cells are transcriptionally inactive. A recent study using a number of different detection techniques now suggests that at least some of the cells nuclei may still be transcriptionally inactive.
Syncytin-1 protein expression occurs in villous and in extravillous trophoblast subpopulations of first- and second-trimester placental tissues and precedes syncytialization of trophoblast cells. (PMID: 19321927) Syncytin-2 is also expressed within the placenta.
References: Ellery PM, Cindrova-Davies T, Jauniaux E, Ferguson-Smith AC, Burton GJ. Evidence for transcriptional activity in the syncytiotrophoblast of the human placenta. Placenta. 2009 Apr;30(4):329-34. Epub 2009 Feb 11. PMID: 19215981
Mesenchymal villi generate all other villous types:
Mesenchymal villi continuously form out of the trophoblastic sprouts throughout pregnancy and have been considered the basis for growth and differentiation of the villous trees.
Trimester 1 and 2
Trimester 3
(Some text modified from PMID: 2327595)
References: Castellucci M, Kosanke G, Verdenelli F, Huppertz B, Kaufmann P. Villous sprouting: fundamental mechanisms of human placental development. Hum Reprod Update. 2000 Sep-Oct;6(5):485-94. Review.PMID: 11045879
During the first trimester of human pregnancy, extravillous trophoblasts (EVT) from placental villi invade the decidua temporarily occluding the spiral arteries. This occusion prevents maternal blood flow and creates a low-oxygen environment, that may play a role in the regulation of extravillous trophoblast outgrowth.
A study has shown that the early placenta ( under 11 weeks of gestation) responds to oxygen concentration, whereas villi from older placentae (11 or 12 weeks) show no differential response. (text modified from: James JL, Stone PR, Chamley LW. The effects of oxygen concentration and gestational age on extravillous trophoblast outgrowth in a human first trimester villous explant model. Hum Reprod. 2006 Oct;21(10):2699-705. Epub 2006 Jun 28.)
Images below show the vascular organisation of the mouse placenta. Note the branching pattern of blood vessels and the relative distribution of arterial and venous vessels within the placenta. Mouse placenta, while being a good model of placentation, will differ in some specific features from that of the human placenta.
Fetal View |
Lateral View Venous side (red resin) and arterial side (blue resin). |
These resin casts are generated by filling the existing vascular beds (day 16.5 p.c.) with a resin that sets and the surrounding materials are then removed, leaving just the vascular beds. Venous side (red resin) and arterial side (blue resin). (More? Placenta Vascular Beds)
Demir R, Demir N, Ustunel I, Erbengi T, Trak I, Kaufmann P. [See Related Articles] The fine structure of normal and ectopic (tubal) human placental villi as revealed by scanning and transmission electron microscopy. Zentralbl Pathol. 1995 Apr;140(6):427-42.
"Structures of placental villi between 28 and 34 days old (pc), early, 6-8 week normal and ectopic, and full term human placenta samples
Three-dimensional configurations of the developing chorionic villous trees were observed as large main villus groups, covered with abundant microvilli of different size and diameters.
Chorionic villous trees which emerged from the chorionic plate divided gradually into branches of which ramifications originated as buds.
Buds gradually grew and were transformed into shoots. The number of developing new villi appeared to increase gradually from 28 days to 9 weeks (pm) of gestation.
4th week onwards the massive trophoblastic sprouts were observed on the surface of main chorionic villi which transformed into primary, secondary and tertiary villous trees.
At term, some specialized structural modifications were observed on the free surface of the mature placental villi. The presence of some dome-like balloonings and many crateriform hollows were the most striking features of the mature intermediate and terminal villi.
According to the increasing physiological needs of the growing fetus, these special structures that are related to lung-like and kidney-like functions and named "nephropneumonic-like units", formed in the mature placental barrier. We have observed that these special units were showing a smooth surface similar to an inflated balloon."
In vitro studies of villi branching show
Fibroblast Growth Factor (FGF10) acting through receptor tyrosine kinase (RTK) receptors promotes invasion and outgrowth of trophoblasts.
Sprouty (Spry2) expression attenuates trophoblast sprouting. Spry2 expression is also increased by FGF10. (PMID: 17496316)
Fibroblast Growth Factor (FGF10) acting through receptor tyrosine kinase (RTK) receptors promotes invasion and outgrowth of trophoblasts.
Sprouty (Spry2) expression attenuates trophoblast sprouting. Spry2 expression is also increased by FGF10. (PMID: 17496316)
Mucin (MUC1) expression increases during human placental development, and an in vitro study also shows that overexpression suppresses trophoblast-like cell invasion. (PMID: 18417712)
Kisspeptins and their receptor are highest in the first trimester in humans (PMID: 17351756)
secreted Frizzled-Related Protein 4 (sFRP4)
Reviews
Aplin JD, Jones CJ, Harris LK. Adhesion molecules in human trophoblast - a review. I. Villous trophoblast. Placenta. 2009 Apr;30(4):293-8. Epub 2009 Jan 7. PMID: 19131106
Huppertz B, Borges M. Placenta trophoblast fusion. Methods Mol Biol. 2008;475:135-47. Review. PMID: 18979242
Kumpel BM, Sibley K, Jackson DJ, White G, Soothill PW. Ultrastructural localization of glycoprotein IIIa (GPIIIa, beta 3 integrin) on placental syncytiotrophoblast microvilli: implications for platelet alloimmunization during pregnancy. Transfusion. 2008 Oct;48(10):2077-86. Epub 2008 Jul 30.
PMID: 18673340
Jirkovská M, Janácek J, Kaláb J, Kubínová L. Three-dimensional arrangement of the capillary bed and its relationship to microrheology in the terminal villi of normal term placenta. Placenta. 2008 Oct;29(10):892-7. Epub 2008 Sep 2. PMID: 18768220
Kalkunte S, Lai Z, Tewari N, Chichester C, Romero R, Padbury J, Sharma S. In vitro and in vivo evidence for lack of endovascular remodeling by third trimester trophoblasts. Placenta. 2008 Oct;29(10):871-8. Epub 2008 Sep 4. PMID: 18775564
Demir R, Demir N, Ustunel I, Erbengi T, Trak I, Kaufmann P. [See Related Articles] The fine structure of normal and ectopic (tubal) human placental villi as revealed by scanning and transmission electron microscopy. Zentralbl Pathol. 1995 Apr;140(6):427-42. Spry proteins are localized in the stroma of the chorionic villi, adjacent to cytotrophoblasts in areas of villous sprouting. placental macrophages (Hofbauer cells) express Spry. Hofbauer cells also expressed c-Cbl, a protein that interacts with Spry. PMID: 15950061
Castellucci M, Scheper M, Scheffen I, Celona A, Kaufmann P. The development of the human placental villous tree. Anat Embryol (Berl). 1990;181(2):117-28
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This current page is an introduction placental villi development.
There is much known about the normal development of placental villi, the "unit" structure of the placenta. Current research though is showing that the textbook descriptions of human placental villi development not be as accurate as once thought.
New Placental Development Page
The cytotrophoblast layer does indeed thin, but it does not become discontinuous at term.
Terminal villi capillary bed arrangement can vary from simple U-like loops to a richly branched network.
Octodon degus and human placentation? The Degu or Chilean ground squirrel is a small caviomorph rodent native to Chile, which may represent a good animal model for human placental development. (PMID: 18512684)
What does placental synthesis of melatonin and local expression of melatonin receptors mean for paracrine/autocrine functions in development? (PMID: 18312298) Possibly acting as a regulator of hCG secretion?
The secreted frizzled-related protein 4 (sFRP4) role in trophoblast development/apoptosis? sFRP4 blocks the Wnt signalling pathway by competitively binding Wnt ligands (frizzled receptors).
Please email Dr Mark Hill if you wish to make a comment about this current project.
