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The cytotrophoblast (or layer of Langhans) is the inner layer of the trophoblast. It is interior to the syncytiotrophoblast and external to the wall of the blastocyst in a developing embryo.

The cytotrophoblast is considered to be the trophoblastic stem cell because the layer surrounding the blastocyst remains while daughter cells differentiate and proliferate to function in multiple roles. There are two lineages that cytotrophoblastic cells may differentiate through: fusion and invasive. The fusion lineage yields syncytiotrophoblast and the invasive lineage yields interstitial cytotrophoblast cells.^[1]

Cytotrophoblastic cells play an important role in the implantation of a newly fertilized egg in the uterus.

Fusion lineage

The formation of all syncytiotrophoblast is from the fusion of two or more cytotrophoblasts via this fusion pathway. This pathway is important because the syncytiotrophoblast plays an important role in fetal-maternal gas exchange, nutrient exchange, and immunological and metabolic functions.

An undifferentiated cytotrophoblastic stem cell will differentiate into a villous cytotrophoblast, which is what constitutes primary chorionic villi, and will eventually coalesce into villous syncytiotrophoblast. The formation of syncytiotrophoblast from cytotrophoblast is a terminal differentiation step of trophoblastic cells.^[2]

Syncytialization of cytotrophoblastic cells can be induced in vitro through multiple signalling molecules including epidermal growth factor, glucocorticoids, and human chorionic gonadotropin.^[3]^[4]^[5]

Invasive lineage

The invasive lineage creates cytotrophoblasts that are essential in the process of implantation and forming a fully functional placenta. An undifferentiated cytotrophoblastic stem cell will differentiate into an extravillous cytotrophoblast intermediate and then into an interstitial cytotrophoblast. An interstitial cytotrophoblast may then further differentiate into an endovascular cytotrophoblast or form a syncytium.^[6]

Interstitial cytotrophoblast

The primary function of an interstitial cytotrophoblast is to anchor the growing fetus to the maternal uterine tissue. These cells may invade the whole endometrium and the proximal third of the myometrium.

Once these cells penetrate through the first few layers of cells of the decidua, they lose their ability to proliferate and become invasive. This departure from the cell cycle seems to be due to factors such as TGF-β and decorin. Although these invasive interstitial cytotrophoblasts can no longer divide, they retain their ability to form syncytia. Multinucleated giant cells (small syncytia) are found in the placental bed and myometrium as a result of the fusion of interstitial cytotrophoblasts.^[7]

Interstitial cytotrophoblasts may also transform into endovascular cytotrophoblasts.

Endovascular cytotrophoblast

The primary function of the endovascular cytotrophoblast is to penetrate maternal spiral arteries and route the blood flow through the placenta for the growing embryo to use.

They arise from interstitial cytotrophoblasts from the process of phenocopying. This changes the phenotype of these cells from epithelial to endothelial. Endovascular cytotrophoblasts, like their interstitial predecessor, are non-proliferating and invasive.

Role in implantation

Proper cytotrophoblast function is essential in the implantation of a blastocyst. After hatching, the embryonic pole of the blastocyst faces the uterine endometrium. Once they make contact the trophoblast begins to rapidly proliferate. The cytotrophoblast secretes proteolytic enzymes to break down the extracellular matrix between the endometrial cells to allow finger-like projections of trophoblast to penetrate through. Projections of cytotrophoblast and syncytiotrophoblast pull the embryo into the endometrium until it is fully covered by endometrial epithelium, save for the coagulation plug.^[8]

Associated disorders

The most common associated disorder is pre-eclampsia, affecting approximately 7% of all births.^[9] It is characterized by a failure of the cytotrophoblast to invade the uterus and its vasculature, specifically the spiral arteries that the endovascular cytotrophoblast should invade. The result of this is decreased blood flow to the fetus which may cause intrauterine growth restriction. Clinical symptoms of pre-eclampsia in the mother are most commonly high blood pressure, proteinuria and edema.

Conversely, if there is too much invasion of uterine tissue by the trophoblast then a hydatidiform mole or choriocarcinoma may arise.

Additional images

Section through embryonic area of Vespertilio murinus to show the formation of the amniotic cavity.

References

^ Handwerger, S. (2010). "New insights into the regulation of human cytotrophoblast cell differentiation." Molecular and Cellular Endocrinology, 323(1), 94-104.
^ Bischof, P., & Irminger-Finger, I. (2005). "The human cytotrophoblastic cell, a mononuclear chameleon." International Journal of Biochemistry & Cell Biology, 37(1), 1-16.
^ Dakour, J., Li, H., Chen, H., & Morrish, D. W. (1999). "EGF promotes development of a differentiated trophoblast phenotype having c-myc and junB proto-oncogene activation." Placenta, 20, 119–126.
^ Cronier, L., Alsat, E., Hervé, J. C., Delèze, J., & Malassiné, A. (1998). "Dexamethasone stimulates gap junctional communication, peptide hormone production and differentiation of human term trophoblast." Trophobl. Res., 11, 35–49.
^ Yang, M., Lei, Z. M., & Rao, Ch. V. (2003). "The central role of human chorionic gonadotropin in the formation of human placental syncytium." Endocrinology, 144, 1108–1120.
^ Bischof, P., & Irminger-Finger, I. (2005). "The human cytotrophoblastic cell, a mononuclear chameleon." International Journal of Biochemistry & Cell Biology, 37(1), 1-16.
^ Bischof, P., & Irminger-Finger, I. (2005). "The human cytotrophoblastic cell, a mononuclear chameleon." International Journal of Biochemistry & Cell Biology, 37(1), 1-16.
^ Schoenwolf, G.C. (2009). Larsen's Human Embryology (pp. 53, 4th Ed.). Philadelphia, PA: Churchill Livingstone.
^ Genbacev, O., DiFederico, E., McMaster, M., & Fisher, S. (1999). "Invasive cytotrophoblast apoptosis in pre-eclampsia." Human Reproduction, 14, 59-66.

External links

Histology image: 19908loa – Histology Learning System at Boston University - "Female Reproductive System: placental villi"
Diagram at McGill

UpToDate Contents

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1. ヒト絨毛性性ゴナドトロピン：妊娠および妊娠性絨毛性疾患の検査と低検査値が持続する原因 human chorionic gonadotropin testing in pregnancy and gestational trophoblastic disease and causes of low persistent levels
2. 胎盤の発達および生理学 placental development and physiology
3. 母体 - 胎児接点の免疫 immunology of the maternal fetal interface
4. 子癇前症：病因 preeclampsia pathogenesis
5. 妊娠性絨毛性疾患：病理 gestational trophoblastic disease pathology

English Journal

STAT3 and ERK Signaling Pathways Are Implicated in the Invasion Activity by Oncostatin M through Induction of Matrix Metalloproteinases 2 and 9.

Ko HS1, Park BJ1, Choi SK1, Kang HK1, Kim A1, Kim HS2, Park IY1, Shin JC3.
Yonsei medical journal.Yonsei Med J.2016 May;57(3):761-8. doi: 10.3349/ymj.2016.57.3.761.
PURPOSE: Our previous studies have shown that oncostatin M (OSM) promotes trophoblast invasion activity through increased enzyme activity of matrix metalloproteinase (MMP)-2 and -9. We further investigated OSM-induced intracellular signaling mechanisms associated with these events in the immortalize
PMID 26996579

Effect of microcystin-LR on human placental villous trophoblast differentiation in vitro.

Douglas GC1, Thirkill TL1, Kumar P1, Loi M1, Hilborn ED2.
Environmental toxicology.Environ Toxicol.2016 Apr;31(4):427-39. doi: 10.1002/tox.22056. Epub 2014 Oct 27.
Microcystin-LR is a cyanobacterial toxin found in surface and recreational waters that inhibits protein phosphatases and may disrupt the cytoskeleton. Microcystins induce apoptosis in hepatocytes at ≤2.0 µM. Nothing is known about the effects of microcystins on human placental trophoblast differe
PMID 25346179

Placenta-on-a-chip: a novel platform to study the biology of the human placenta.

Lee JS1, Romero R2,3,4,5, Han YM6, Kim HC7,8,9, Kim CJ10, Hong JS6, Huh D11.
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.J Matern Fetal Neonatal Med.2016 Apr;29(7):1046-54. doi: 10.3109/14767058.2015.1038518. Epub 2015 Jun 15.
OBJECTIVE: Studying the biology of the human placenta represents a major experimental challenge. Although conventional cell culture techniques have been used to study different types of placenta-derived cells, current in vitro models have limitations in recapitulating organ-specific structure and ke
PMID 26075842

Japanese Journal

3) 血管内皮から観た妊娠高血圧症候群の病態とその発症予知(シンポジウム2:周産期「妊娠高血圧症候群の基礎と臨床-予防・治療の新戦略に向けて」,第65回日本産科婦人科学会・学術講演会)

松原圭一
日本産科婦人科學會雜誌 65(11), 2591-2603, 2013-11-01
… Pregnancy induced hypertension(PIH) is characterized by the failure of cytotrophoblast infiltration into decidua. …
NAID 110009674983

3) 血管内皮から観た妊娠高血圧症候群の病態とその発症予知(シンポジウム2:周産期「妊娠高血圧症候群の基礎と臨床-予防・治療の新戦略に向けて」,第65回日本産科婦人科学会・学術講演会)

松原圭一
日本産科婦人科學會雜誌 65(11), 2591-2603, 2013-11-01
… Pregnancy induced hypertension(PIH) is characterized by the failure of cytotrophoblast infiltration into decidua. …
NAID 110009661871

Oxidative Stress Produced by Xanthine Oxidase Induces Apoptosis in Human Extravillous Trophoblast Cells

, , [他], , ,
Journal of Reproduction and Development 59(1), 7-13, 2013
… It has been reported that the expression of xanthine oxidase (XO) in the cytotrophoblast and plasma hydrogen peroxide (H2O2) level are significantly higher in preeclamptics than in control women. …
NAID 130001854936

Related Pictures

Cytotrophoblast Related Keywords - Cytotrophoblast Long Tail Keywords KeywordsKing Chapter 2: Second Week - Biological Sciences 484 with Chapman at Clemson University Implantation of the Egg | Lithopedion Fertilization & Preimplantation at Wright State University - StudyBlue Early Embryology at Kirksville College of Osteopathic Medicine - StudyBlue Embryology: Formation of the Bilaminar Germ Disk Flashcards | Quizlet Implantation (General Embryology)

★リンクテーブル★

リンク元	「細胞性栄養膜細胞」「栄養膜細胞層」「細胞栄養芽層」

「細胞性栄養膜細胞」

Cytotrophoblast
	Primary chorionic villi. Diagrammatic.
	Secondary chorionic villi. Diagrammatic.
Details
Carnegie stage	5a
Days	8
Identifiers
Latin	cytotrophoblastus
MeSH	D014327
TE	E6.0.1.1.4.0.5
FMA	83039
	Anatomical terminology [edit on Wikidata]

　　[★]

英: cytotrophoblast
同: Langhans細胞, 細胞性トロホブラスト
関: 栄養膜細胞

着床後、栄養膜細胞が栄養膜細胞層と栄養膜合胞体層に分かるが、前者を特に指していう言葉と思われる。

Henry Gray (1825-1861). Anatomy of the Human Body. 1918.

「栄養膜細胞層」

　　[★]

英: cytotrophoblast
ラ: cytotrophoblastus
同: 細胞栄養層、ラングハンス層 Langhans layer
関: 栄養膜

「細胞栄養芽層」

　　[★]

英: cytotrophoblast
関: 栄養芽細胞、シンシチウム栄養芽層

[1] Handwerger, S. (2010). "New insights into the regulation of human cytotrophoblast cell differentiation." Molecular and Cellular Endocrinology, 323(1), 94-104.

[2] Bischof, P., & Irminger-Finger, I. (2005). "The human cytotrophoblastic cell, a mononuclear chameleon." International Journal of Biochemistry & Cell Biology, 37(1), 1-16.

[3] Dakour, J., Li, H., Chen, H., & Morrish, D. W. (1999). "EGF promotes development of a differentiated trophoblast phenotype having c-myc and junB proto-oncogene activation." Placenta, 20, 119–126.

[4] Cronier, L., Alsat, E., Hervé, J. C., Delèze, J., & Malassiné, A. (1998). "Dexamethasone stimulates gap junctional communication, peptide hormone production and differentiation of human term trophoblast." Trophobl. Res., 11, 35–49.

[5] Yang, M., Lei, Z. M., & Rao, Ch. V. (2003). "The central role of human chorionic gonadotropin in the formation of human placental syncytium." Endocrinology, 144, 1108–1120.

[6] Bischof, P., & Irminger-Finger, I. (2005). "The human cytotrophoblastic cell, a mononuclear chameleon." International Journal of Biochemistry & Cell Biology, 37(1), 1-16.

[7] Bischof, P., & Irminger-Finger, I. (2005). "The human cytotrophoblastic cell, a mononuclear chameleon." International Journal of Biochemistry & Cell Biology, 37(1), 1-16.

[8] Schoenwolf, G.C. (2009). Larsen's Human Embryology (pp. 53, 4th Ed.). Philadelphia, PA: Churchill Livingstone.

[9] Genbacev, O., DiFederico, E., McMaster, M., & Fisher, S. (1999). "Invasive cytotrophoblast apoptosis in pre-eclampsia." Human Reproduction, 14, 59-66.

v t e Membranes of the fetus and embryo
Embryo	Trophoblast Cytotrophoblast Syncytiotrophoblast Intermediate trophoblast Allantois Decidua Decidual cells Chorionic villi/Intervillous space Amnion sac cavity
Fetus	Umbilical cord Umbilical artery Umbilical vein Wharton's jelly
Circulatory	Placenta Chorion
Other	Blastocoel Heuser's membrane Vitelline duct Gestational sac

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cytotrophoblast