Trophoblast lineage specification, differentiation and their regulation by oxygen tension

Development of the early embryo takes place under low oxygen tension. Under such conditions, the embryo implants and the trophectoderm, the outer layer of blastocyst, proliferate, forming the cytotrophoblastic shell, the early placenta. The cytotrophoblasts (CTBs) are the so-called epithelial ‘stem cells’ of the placenta, which, depending on the signals they receive, can differentiate into either extravillous trophoblast (EVT) or syncytiotrophoblast (STB). EVTs anchor the placenta to the uterine wall and remodel maternal spiral arterioles in order to provide ample blood supply to the growing fetus. STBs arise through CTB fusion, secrete hormones necessary for pregnancy maintenance and form a barrier across which nutrient and gas exchange can take place. The bulk of EVT differentiation occurs during the first trimester, before the onset of maternal arterial blood flow into the intervillous space of the placenta, and thus under low oxygen tension. These conditions affect numerous signaling pathways, including those acting through hypoxia-inducible factor, the nutrient sensor mTOR and the endoplasmic reticulum stress-induced unfolded protein response pathway. These pathways are known to be involved in placental development and disease, and specific components have even been identified as directly involved in lineage-specific trophoblast differentiation. Nevertheless, much controversy surrounds the role of hypoxia in trophoblast differentiation, particularly with EVT. This review summarizes previous studies on this topic, with the intent of integrating these results and synthesizing conclusions that resolve some of the controversy, but then also pointing to remaining areas, which require further investigation.

Download Full-text

Low oxygen enhances trophoblast column growth by potentiating the extravillous lineage and promoting LOX activity

10.1101/669796 ◽

2019 ◽

Author(s):

Jenna Treissman ◽

Victor Yuan ◽

Jennet Baltayeva ◽

Hoa T. Le ◽

Barbara Castellana ◽

...

Keyword(s):

Lysyl Oxidase ◽

Atmospheric Oxygen ◽

Extravillous Trophoblast ◽

Low Oxygen ◽

Placental Development ◽

Trophoblast Differentiation ◽

Expression Of Genes ◽

Summary Statement ◽

Insight Into

ABSTRACTEarly placental development and the establishment of the invasive trophoblast lineage take place within a low oxygen environment. However, conflicting and inconsistent findings have obscured the role of oxygen in regulating invasive trophoblast differentiation. In this study, the effect of hypoxic, normoxic, and atmospheric oxygen on invasive extravillous pathway progression was examined using a human placental explant model. Here, we show that exposure to low oxygen enhances extravillous column outgrowth and promotes the expression of genes that align with extravillous trophoblast (EVT) lineage commitment. By contrast, super-physiological atmospheric levels of oxygen promote trophoblast proliferation while simultaneously stalling EVT progression. Low oxygen-induced EVT differentiation coincided with elevated transcriptomic levels of lysyl oxidase (LOX) in trophoblast anchoring columns, where functional experiments established a role for LOX activity in promoting EVT column outgrowth. The findings of this work support a role for low oxygen in potentiating the differentiation of trophoblasts along the extravillous pathway. Additionally, these findings generate insight into new molecular processes controlled by oxygen during early placental development.Summary StatementLow oxygen promotes extravillous trophoblast differentiation

Download Full-text

HYPOXIA AND REPRODUCTIVE HEALTH: Oxygen and development of the human placenta

Reproduction ◽

10.1530/rep-20-0153 ◽

2021 ◽

Vol 161 (1) ◽

pp. F53-F65 ◽

Cited By ~ 2

Author(s):

Graham J Burton ◽

Tereza Cindrova-Davies ◽

Hong wa Yung ◽

Eric Jauniaux

Keyword(s):

Oxidative Stress ◽

Human Placenta ◽

Epithelial Mesenchymal Transition ◽

First Trimester ◽

Extravillous Trophoblast ◽

Low Oxygen ◽

Placental Development ◽

Mesenchymal Transition ◽

Oxygen Concentrations

Development of the human placenta takes place in contrasting oxygen concentrations at different stages of gestation, from ~20 mmHg during the first trimester rising to ~60 mmHg at the start of the second trimester before gradually declining to ~40 mmHg at term. In view of these changes, the early placenta has been described as ‘hypoxic’. However, placental metabolism is heavily glycolytic, supported by the rich supply of glucose from the endometrial glands, and there is no evidence of energy compromise. On the contrary, the trophoblast is highly proliferative, with the physiological low-oxygen environment promoting maintenance of stemness in progenitor populations. These conditions favour the formation of the cytotrophoblastic shell that encapsulates the conceptus and interfaces with the endometrium. Extravillous trophoblast cells on the outer surface of the shell undergo an epithelial-mesenchymal transition and acquire invasive potential. Experimental evidence suggests that these changes may be mediated by the higher oxygen concentration present within the placental bed. Interpreting in vitro data is often difficult, however, due to the use of non-physiological oxygen concentrations and trophoblast-like cell lines or explant models. Trophoblast is more vulnerable to hyperoxia or fluctuating levels of oxygen than to hypoxia, and some degree of placental oxidative stress likely occurs in all pregnancies towards term. In complications of pregnancy, such as early-onset pre-eclampsia, malperfusion generates high levels of oxidative stress, causing release of factors that precipitate the maternal syndrome. Further experiments are required using genuine trophoblast progenitor cells and physiological concentrations to fully elucidate the pathways by which oxygen regulates placental development.

Download Full-text

Oxygen governs Galβ1–3GalNAc epitope in human placenta

AJP Cell Physiology ◽

10.1152/ajpcell.00407.2012 ◽

2013 ◽

Vol 305 (9) ◽

pp. C931-C940 ◽

Cited By ~ 8

Author(s):

Leonardo Ermini ◽

Jayonta Bhattacharjee ◽

Antonella Spagnoletti ◽

Nicoletta Bechi ◽

Silvia Aldi ◽

...

Keyword(s):

Oxygen Tension ◽

Human Placenta ◽

Physiological State ◽

First Trimester ◽

Signal Molecules ◽

Control Mechanisms ◽

Low Oxygen ◽

Placental Development ◽

Human Trophoblast ◽

Cell Functions

It is becoming increasingly apparent that the dynamics of glycans reflect the physiological state of cells involved in several cell functions including growth, response to signal molecules, migration, as well as adhesion to, interaction with, and recognition of other cells. The presence of glycoconjugates in human placenta suggests their major role in maternal-fetal exchanges, intercellular adhesion, cellular metabolism, and villous vessel branching. Although several studies have described glycoconjugate distribution in the human placenta descriptions of their physiological function and control mechanisms during placental development are lacking. In this study we investigated the developmental distribution and regulation of placental core 1 O- and N-glycans focusing on early and late first trimester human pregnancy. To define the control mechanisms of the oligosaccharide chains during early placentation process, chorionic villous explants and human trophoblast cell lines were exposed to various oxygen levels. We found that oxygen tension regulates changes in core-1 O-glycan (the disaccharide Galβ1–3GalNAc) epitope expression levels. Moreover, by double affinity chromatography and subsequent analysis with mass spectrometry, we identified in the heat shock protein 90-α (HSP90α) a good candidate as carrier of the Galβ1–3GalNAc epitope at low oxygen tension. Our results support a fundamental role of oxygen tension in modulating glycosylation of proteins during placental development.

Download Full-text

Low oxygen tension may increase implantation potential by enhanced expression of hypoxia and antioxidant genes in mouse blastocyst cultured in vitro

10.26226/morressier.573c1511d462b80296c983c5 ◽

2016 ◽

Author(s):

Yun Yi Ma

Keyword(s):

Oxygen Tension ◽

Low Oxygen ◽

Mouse Blastocyst ◽

Antioxidant Genes ◽

Low Oxygen Tension ◽

Enhanced Expression

Download Full-text

Low oxygen tension potentiates proliferation and stemness but not multilineage differentiation of caprine male germline stem cells

Molecular Biology Reports ◽

10.1007/s11033-021-06501-y ◽

2021 ◽

Author(s):

Shiva Pratap Singh ◽

Suresh Dinkar Kharche ◽

Manisha Pathak ◽

Ravi Ranjan ◽

Yogesh Kumar Soni ◽

...

Keyword(s):

Stem Cells ◽

Oxygen Tension ◽

Germline Stem Cells ◽

Multilineage Differentiation ◽

Low Oxygen ◽

Male Germline ◽

Low Oxygen Tension ◽

Male Germline Stem Cells

Download Full-text

A brief very-low oxygen tension regimen is sufficient for the early chondrogenic commitment of human adipose-derived mesenchymal stem cells

Advances in Medical Sciences ◽

10.1016/j.advms.2020.12.005 ◽

2021 ◽

Vol 66 (1) ◽

pp. 98-104 ◽

Cited By ~ 1

Author(s):

Marco Govoni ◽

Claudio Muscari ◽

Francesca Bonafè ◽

Paolo Giovanni Morselli ◽

Marilisa Cortesi ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Oxygen Tension ◽

Low Oxygen ◽

Low Oxygen Tension

Download Full-text

Oxygen regulation of macrophage migration inhibitory factor in human placenta

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00086.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. E272-E280 ◽

Cited By ~ 23

Author(s):

Francesca Ietta ◽

Yuanhong Wu ◽

Roberta Romagnoli ◽

Nima Soleymanlou ◽

Barbara Orsini ◽

...

Keyword(s):

High Altitude ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Inhibitory Factor ◽

Extravillous Trophoblast ◽

Macrophage Migration ◽

Low Oxygen ◽

Placental Development

Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine involved in regulation of macrophage function. In addition, MIF may also play a role in murine and human reproduction. Although both first trimester trophoblast and decidua express MIF, the regulation and functional significance of this cytokine during human placental development remains unclear. We assessed MIF expression throughout normal human placental development, as well as in in vitro (chorionic villous explants) and in vivo (high altitude placentae) models of human placental hypoxia. Dimethyloxalylglycine (DMOG), which stabilizes hypoxia inducible factor-1 under normoxic conditions, was also used to mimic the effects of hypoxia on MIF expression. Quantitative real-time PCR and Western blot analysis showed high MIF protein and mRNA expression at 7–10 wk and lower levels at 11–12 wk until term. Exposure of villous explants to 3% O2 resulted in increased MIF expression and secretion relative to standard conditions (20% O2). DMOG treatment under 20% O2 increased MIF expression. In situ hybridization and immunohistochemistry showed elevated MIF expression in low oxygen-induced extravillous trophoblast cells. Finally, a significant increase in MIF transcript was observed in placental tissues from high-altitude pregnancies. Hence, three experimental models of placental hypoxia (early gestation, DMOG treatment, and high altitude) converge in stimulating increased MIF, supporting the conclusion that placental-derived MIF is an oxygen-responsive cytokine highly expressed in physiological in vivo and in in vitro low oxygen conditions.

Download Full-text