UNSW Embryology

Placenta Molecular Development

© Dr Mark Hill (2010)

Acknowledgements

Introduction

The placenta (Greek, plakuos = flat cake) named on the basis of this organs appearance. The placenta a mateno-fetal organ which begins developing at implantation of the blastocyst and is delivered with the fetus at birth.

The placenta at birth has recently been seen as a new source for cells in bone marrow replacement therapy in many diseases. (More? Stem Cells - Cord Blood)

Page Links: Introduction | Recent Findings | Molecular Trophoblast Development | Placenta Specific Genes | Terms | Glossary |References | About Notes |

Related Pages: Villi Development | Maternal Decidua | Placental Abnormalities | Stage 13/14 | Stage22 | Placental Histology | Placental Vascular Beds | Blood | Blood Vessels | Birth | Stem Cells - Cord Blood

Some Recent Findings

SUMO-specific protease 2 is essential for modulating p53-Mdm2 in development of trophoblast stem cell niches and lineages. Chiu SY, Asai N, Costantini F, Hsu W. PLoS Biol. 2008 Dec 16;6(12):e310.

"SUMO-specific protease 2 (SENP2) modifies proteins by removing SUMO from its substrates. Although SUMO-specific proteases are known to reverse sumoylation in many defined systems, their importance in mammalian development and pathogenesis remains largely elusive. Here we report that SENP2 is highly expressed in (mouse) trophoblast cells that are required for placentation."

Trophoblast stem cell derivation, cross-species comparison and use of nuclear transfer: new tools to study trophoblast growth and differentiation. Rielland M, Hue I, Renard JP, Alice J. Dev Biol. 2008 Oct 1;322(1):1-10. Epub 2008 Jul 22. Review.

Molecular Trophoblast Development

Model for the SENP2–Mdm2–p53 Pathway in Trophoblast Development

(A) Diagram illustrating the p53–Mdm2 circuit regulated by SENP2 in the trophoblast cell cycle. Stimulation of Mdm2 by SENP2 leads to degradation of p53. Cellular levels of p53 control the G–S transition that has a dual role in TGC development. The G–S phase is required for both mitotic division (cell cycle: G1, S, G2, and M) and endoreduplication (endocycle: G and S only) during expansion of trophoblast stem cells and maturation of trophoblasts, respectively. Although a low p53 level is essential for stem cell proliferation, inhibition of p53 is required upon differentiation.

(B) Schematic representation for the mechanism underlying the regulation of p53 and Mdm2 by the SUMO pathway. SENP2 activates Mdm2 by removing SUMO that permits the modulation of p53 by Mdm2 in the nucleus. The ubiquitin-conjugated p53 is then degraded in the cytoplasm.

From: SUMO-Specific Protease 2 Is Essential for Modulating p53-Mdm2 in Development of Trophoblast Stem Cell Niches and Lineages Chiu SY, Asai N, Costantini F, Hsu W PLoS Biology Vol. 6, No. 12, e310 doi:10.1371/journal.pbio.0060310

SUMO - Small Ubiquitin-like Modifier are a family of small proteins that modify the function of other proteins by covalently attaching to and detaching from the other proteins.

SUMOylation - a post-translational protein modification involving SUMO proteins and has a role in many different cellular processes.

Placenta Specific Genes

placenta-specific genes: Tpbp, Plac1, Syncytin

retrotransposon-associated genes: Peg10, Rtl1, Endothelin B receptor, Insl4, Leptin, Midline1, and Pleiotrophin

enhancer elements: glycoprotein hormone alpha-subunit

gene isoforms: 3betaHSD, Cyp19

placenta-specific members of gene families: Gcm1, Mash2, Rhox, Esx1, Cathepsin, PAG, TKDP, Psg, Siglec

(Gene list from : The evolution, regulation, and function of placenta-specific genes. Rawn SM, Cross JC. Annu Rev Cell Dev Biol. 2008;24:159-81. Review)

Placental Types

Discoid in humans, mice, insectivores, rabbits, rats, and monkeys.

Zonary in dogs, cats, bears and seals.

Cotyledenary in cows, deer, goat, and giraffe.

Diffuse in horses, pigs, camels, lemurs, opossums, kangaroos, and whales.

(List modified from Dev Biology after Renfree, 1982 | four main types of placenta in different species)

Placental Layers

Hemochorial placentas (maternal blood cells directly contacts fetal chorion) in humans, rats, and mice.

Endotheliochorial placentas (4 layer) in dogs, cats, seals, and ferrets.

Epitheliochorial placentas (6-layer) in pigs, cows, horses, and sheep.

(List modified from Dev Biology after Renfree, 1982 | cellular layers potentially between the fetal and maternal blood cells )

Fetal Placenta

	Trophoblast cells are the major source of placental hormones. Placental growth hormone (PGH) is mainly expressed in the syncytiotrophoblast cells (PGH differs from pituitary derived growth hormone by 13 amino acids). extravillous cytotrophoblast - arise from anchoring villi invade the uterine spiral arteries, generating fibrinoid material and endovascular trophoblastic cells. syncytiotrophoblast
	Fetal Blood Vessels At least 2 phases of development during pregnancy driven by vascular endothelial growth factor (VEGF): Initially cytotrophoblasts are the cellular stimulus to vasculogenesis and angiogenesis. Later Hofbauer and stromal cells take over the stimulation of blood vessel development.

Maternal Placenta

Fibrinoid - said to exist as 2 forms of extracellular matrix: Fibrin-type fibrinoid is a maternal blood-clot product which replaces degenerative syncytiotrophoblast Matrix-type fibrinoid is secreted by invasive extravillous trophoblast cells. This fibrinoid layer (Nitabuch's layer) is thought to act to prevent excessively deep implantation. Decidualization - process of endometrial stromal cells (fibroblast-like) change in morphology (polygonal cells) and protein expression (specific decidual proteins) forming decidual cells.

Estrogen and progesterone - receptive phase, luminal and glandular epithelial cells change in preparation for blastocyst adplantation. Human Chorionic gonadotropin - luminal epithelium endoreplication leading to epithelial plaque formation. Human Chorionic gonadotropin - trophoblast invasion and decidualization of human stromal fibroblasts.

Endoreplication - rounds of nuclear DNA replication without intervening cell or nuclear division (mitosis). Cytokines - of maternal origin also act on placental development. Natural Killer (NK) cells - are present in the maternal decidua in large numbers close to the extravillous trophoblast cells.

Maternal Decidual Cells are differentiated by progesterone from endometrial stromal cells (fibroblast-like). These cells change morphology (become enlarged and polygonal) and secrete various factors (prolactin, insulin-like growth factor binding protein-1, tissue factor, interleukin-15, and vascular endothelial growth factor).

Development Overview

• Maternal Surface
  • Cotyledons - form cobblestone appearance
  • originally placental septa formed grooves
  • covered with maternal decidua basalis
• Fetal Surface
  • umbilical cord attachment
  • cord 1-2 cm diameter, 30-90cm long
  • covered with amniotic attached to chorionic plate
  • umbilical vessels branch into chorionic vessels which anastomose
• Chorionic Villi-Primary Villi
  • week 2
  • trophoblastic shell cells
  • syncitiotrophoblasts, cytotrophoblasts
  • form finger-like extensions
• Chorionic Villi- Secondary Villi
  • week 3
  • extraembryonic mesoderm grows into villi
  • covers entire surface of chorionic sac
• Chorionic Villi- Tertiary Villi
  • mesenchyme differentiates into blood vessels and cells
  • forms arteriocapillary network
  • fuse with placental vessels
  • developing in connecting stalk
• Chorionic Villi
  • Stem
    • or anchoring villi
    • cytotrophoblast cells attached to maternal tissue
  • Branched
    • or terminal villi
    • grow from sides of stem villi
    • region of main exchange
  • surrounded by maternal blood in intervillous spaces
  • maternal sinusoids
• Chorionoic Villi
  • originally cover entire chorionic surface
  • become restricted to decidua basalis region
  • Frondosum
  • Capsularis
• Maternal Decidua basalis reaction
  • deposition of glycogen
  • proliferation of blood vessels
  • artery dilatation
    • due to extravillous trophoblast cells invading uterine wall and maternal spiral arteries replacing both smooth muscle with fibrinoid material and part of vessel endothelium
• Placental Function
  • 4 layers separate maternal and fetal blood
    • syncitiotrophoblast
    • cytotrophoblast
    • villi connective tissue
    • fetal capillary endothelium
  • 3 main functions
    • metabolism
    • transport
    • endocrine
• Placental Endocrine
  • Human chorionic gonadotrophin (hCG)
    • like leutenizing hormone, supports corpus luteum
  • Human chorionic somatommotropin (hCS)
    • or placental lactogen
    • hormone level increases in maternal blood through pregnancy
    • decreases maternal insulin sensitivity (raising maternal blood glucose levels and decreasing maternal glucose utilization) aiding fetal nutrition
    • "anti-insulin" function
  • Human chorionic thyrotropin (hCT)
    • (hCT) Peptide placental hormone, similar to anterior pituitary released thyroid stimulating hormone (TSH), which along with human chorionic gonadotrophin (hCG) is thought to act on maternal thyroid. There is little recent research published on this hormone, its level and activities.
  • Human chorionic corticotropin (hCACTH)
    • placental hormone thought to have corticotropin (ACTH)-like activity, increasing maternal cortisol levels.
  • Steroid Hormones
    • progestins - progesterone, support of the endometrium and suppress uterine smooth muscle contractility.
    • estrogens - estriol, stimulate growth of the myometrium and mammary gland development.
  • both hormones support maternal endometrium
  • Relaxin – Humans high levels early in pregnancy than at birth promotes angiogenesis probably plays a role in development of the uterus/ placenta than in the birth process
• Placental Blood vessels

References

Reviews

• Trophoblast stem cell derivation, cross-species comparison and use of nuclear transfer: new tools to study trophoblast growth and differentiation. Rielland M, Hue I, Renard JP, Alice J. Dev Biol. 2008 Oct 1;322(1):1-10. Epub 2008 Jul 22. Review.
• The evolution, regulation, and function of placenta-specific genes. Rawn SM, Cross JC. Annu Rev Cell Dev Biol. 2008;24:159-81. Review
• Vogel P.    [See Related Articles] The current molecular phylogeny of Eutherian mammals challenges previous interpretations of placental evolution. Placenta. 2005 Sep-Oct;26(8-9):591-6.
• Cross JC.    [See Related Articles] How to make a placenta: mechanisms of trophoblast cell differentiation in mice--a review. Placenta. 2005 Apr;26 Suppl A:S3-9.
• Simmons DG, Cross JC.    [See Related Articles] Determinants of trophoblast lineage and cell subtype specification in the mouse placenta. Dev Biol. 2005 Aug 1;284(1):12-24.
• Genes, development and evolution of the placenta.Cross JC, Baczyk D, Dobric N, Hemberger M, Hughes M, Simmons DG, Yamamoto H, Kingdom JC. Placenta. 2003 Feb-Mar;24(2-3):123-30. Review.

Articles

• SUMO-specific protease 2 is essential for modulating p53-Mdm2 in development of trophoblast stem cell niches and lineages. Chiu SY, Asai N, Costantini F, Hsu W. PLoS Biol. 2008 Dec 16;6(12):e310.
• Wu S, Kocherginsky M, Hibbard JU.   [See Related Articles] Abnormal placentation: twenty-year analysis. Am J Obstet Gynecol. 2005 May;192(5):1458-61.
• Weier JF, Weier HU, Jung CJ, Gormley M, Zhou Y, Chu LW, Genbacev O, Wright AA, Fisher SJ.   [See Related Articles] Human cytotrophoblasts acquire aneuploidies as they differentiate to an invasive phenotype. Dev Biol. 2005 Mar 15;279(2):420-32.
• Kayisli UA, Cayli S, Seval Y, Tertemiz F, Huppertz B, Demir R.   [See Related Articles] Spatial and Temporal Distribution of Tie-1 and Tie-2 During Very Early Development of the Human Placenta. Placenta. 2005 Jul 15
• Jishage KI, Tachibe T, Ito T, Shibata N, Suzuki S, Mori T, Hani T, Arai H, Suzuki H.   [See Related Articles] Vitamin E Is Essential for Mouse Placentation but not for Embryonic Development Itself. Biol Reprod. 2005 Jul
• Dimitriadis E, White CA, Jones RL, Salamonsen LA.   [See Related Articles] Cytokines, chemokines and growth factors in endometrium related to implantation. Hum Reprod Update. 2005 Jul 8
• van den Brule F, Berndt S, Simon N, Coulon C, Le Goarant J, Munaut C, Noel A, Frankenne F, Foidart JM.    [See Related Articles] Trophoblast invasion and placentation: molecular mechanisms and regulation. Chem Immunol Allergy. 2005;88:163-80.

Search PubMed: Search term = placenta molecular development

Glossary of Terms

A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z

Placenta Development Terms

• anastomose
• angiogenesis development of new vessels from already existing vessels, this process is secondary to vasculogenesis which is the initial formation of first blood vessels by differentiation of pluripotent mesenchymal cells (extraembryonic mesoderm).
• angioblasts form clusters or blood islands on surface of yolk sac.
• capsularis
• chorionic sac fetal membrane that surrounds the developing embryo.
• cord knotting umbilical cord knotting occurs in 1%, prevents the passage of placental blood. pseudoknots also occur usually with no effect.
• cotyledons maternal side cobblestone appearance, originally placental septa formed grooves is covered with maternal decidua basalis.
• cytotrophoblast extraembryonic cells of trophoblastic shell surrounding embryo, contribute to villi and placental membranes.
• decidua basalis reaction occurs in maternal endometrium at site of, and following, blastocyst implantation. Seen as a deposition of glycogen and proliferation of blood vessels. (see also decidualization)
• decidualization process by which uterine stromal cells differentiate in response to both steroid hormones and embryonic signals into large epitheliod decidual cells. This process is essential for the progress of implantation and establishing fetal-maternal communication.
• endocrine function of placenta:
  • Human chorionic gonadotrophin (hCG) like leutenizing hormone, supports corpus luteum
  • Human chorionic somatommotropin (hCS) or placental lactogen, stimulate mammary development
  • Human chorionic thyrotropin (hCT)
  • Human chorionic corticotropin (hCACTH)
  • progesterone and estrogens support maternal endometrium
  • relaxin- role in parturition, softens ligaments
• fetal drug addiction occurs when drugs used maternally cross the placental barrier and can establish addiction in the unborn fetus.
• fetal erythroblastosis (Haemolytic Disease of the Newborn), an immune problem from fetus Rh+ /maternal Rh-, leakage from fetus causes anti-Rh antibodies, which is then dangerous for a 2nd child.
• frondosum-
• haemocytoblasts (hemangioblast) stem cells for embryonic blood cell formation, often appearing as a "cluster" or "island".
• Haemolytic Disease of the Newborn- see fetal erythroblastosis.
• Hofbauer cells - placental villi macrophages of mesenchymal origin with potentially additional functions (vasculogenesis/angiogenesis, villi remodeling, regulation of stromal water content) to their macrophage role.
• Human chorionic gonadotrophin- (hCG) like leutenizing hormone, supports corpus luteum
• Human chorionic somatommotropin - (hCS) or placental lactogen - hormone level increases in maternal blood through pregnancy, decreases maternal insulin sensitivity (raising maternal blood glucose levels and decreasing maternal glucose utilization) aiding fetal nutrition.
• Human chorionic thyrotropin- (hCT) placental derived hormone equivilant to thyroid
• Human chorionic corticotropin- (hCACTH) placental derived hormone equivilant to corticotropin (ACTH) from the pituitary.
• maternal antibodies- antibodies from the mother's immune system that are capable of crossing placental barrier. They can provide immune protection to the embryo, but may also participate in immune disease (fetal erythroblastosis).
• maternal sinusoids- placental spaces around chorionic villi that are filled with maternal blood. Closest maternal/fetal exchange site.
• Nitabuch's layer (fibrinoid layer) layer formed at maternal/fetal interface during placentation and is thought to act to prevent excessively deep conceptus implantation. Fibrin-type fibrinoid (maternal blood-clot product) and matrix-type fibrinoid (secreted by invasive extravillous trophoblast cells).
• placenta- (Gk. plakuos= flat cake) describes its typical mature discoid shape (20cm diameter and 3 cm thick at term,weighs 500-600 gm).
• placenta accreta- abnormal, adherence with absence of decidua basalis.
• placental arteries- paired, carry deoxygenated blood and waste from the embryo (dorsal aorta->internal iliacs->PA)
• placental blood- blood found within the placental vessels. Obviously part of the fetal blood, but can be collected at birth for theraputic use containing blood stem cells (see cord blood banks).
• placental blood vessels- form initially in the connecting stalk (then umbilical cord), anastomose in chorioni and extend maternally toward chorionic villi, extend embryonically to the sinus venosus and dorsal aorta.
• placental layers- 4 layers separate maternal and fetal blood: syncitiotrophoblast, cytotrophoblast, villi connective tissue, and fetal capillary endothelium.
• placenta percreta- abnormal, villi penetrate myometrium.
• placenta previa- placenta overlies internal os of uterus, abnormal bleeding, may require cesarian delivery.
• placental veins- paired initially then usually only one left at end of embryonic period, carry oxygenated blood to the embryo (sinus venosus)
• primary villi- develop week 2, consist of trophoblastic shell cells both syncitiotrophoblasts and cytotrophoblasts. Form finger-like extensions into the maternal endometrium.
• protein hormone- usually a protein distributed in the blood that binds to membrane receptors on target cells in different tissues. Do not easliy cross placental barrier.
• relaxin- hormone.
• secondary villi- develop week 3, extraembryonic mesoderm grows into villi, initially covers entire surface of chorionic sac.
• sinus venosus- cavity into which all major embryonic paired veins supply (vitelline, placental, cardinal)
• SUMO - Small Ubiquitin-like Modifier are a family of small proteins that modify the function of other proteins by covalently attaching to and detaching from the other proteins.
• SUMOylation - a post-translational protein modification involving SUMO proteins and has a role in many different cellular processes.
• syncitiotrophoblast- extraembryonic cells of trophoblastic shell surrounding embryo, outside the cytotrophoblast layer, involved with implantation of the blastocyst by eroding extracellular matrix surrounding maternal endometrial cells at site of implantation, also contribute to villi. (dark staining, multinucleated)
• tertiary villi- develop week 4, mesenchyme within secondary villi differentiates into blood vessels and cells, forms arteriocapillary network, fuse with placental vessels developing in connecting stalk.
• trophoblast-
• umbilical cord- fetal attachment cord 1-2 cm diameter, 30-90cm long, covered with amniotic attached to chorionic plate, umbilical vessels (artery, vein) branch into chorionic vessels. Vessels anastomose within the placenta.
• vasculogenesis formation of first blood vessels by differentiation of pluripotent mesenchymal cells (extraembryonic mesoderm) followed by angiogenesis which is the development of new vessels from already existing vessels.
• villi- initially outgrowth of the trophoblastic shell which involve other tissues with development. Develop in sequence (primary, secondary, tertiary) with mature villi being stem por branched type.
• virus- small infectious agent able to cross placental barrier. Can infect embryo and cause developmental abnormalities. (e.g. cytomegalovirus, rubella, measles)
• vitelline- Blood vessels cover entire surface of yolk sac and connect to embryo through yolk stalk
  • Arteries- arises from dorsal aorta and contribute to adult GIT arteries.
  • Veins- empties into sinus venosus and contribute to the adult portal system.
• waste products- products of cellular metabolism and cellular debris, e.g.- urea, uric acid, bilirubin
• Wharton's jelly placental cord (umbilical cord) gelatinous connective tissue composed of myofibroblast-like stromal cells, collagen fibers, and proteoglycans. Increases in volume (myxomatous, connective tissue embedded in mucus) at parturition to assist closure of placental blood vessels. Matrix cells from Wharton's jelly have recently been identified as a potential source of stem cells. This placental cord substance is named after Thomas Wharton (1614-1673) an English physician and anatomist who first described it.

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