123 research outputs found
Modeling human trophoblast, the placental epithelium at the maternal fetal interface.
Appropriate human trophoblast lineage specification and differentiation is crucial for the establishment of normal placentation and maintenance of pregnancy. However, due to the lack of proper modeling systems, the molecular mechanisms of these processes are still largely unknown. Much of the early studies in this area have been based on animal models and tumor-derived trophoblast cell lines, both of which are suboptimal for modeling this unique human organ. Recent advances in regenerative and stem cell biology methods have led to development of novel in vitro model systems for studying human trophoblast. These include derivation of human embryonic and induced pluripotent stem cells and establishment of methods for the differentiation of these cells into trophoblast, as well as the more recent derivation of human trophoblast stem cells. In addition, advances in culture conditions, from traditional two-dimensional monolayer culture to 3D culturing systems, have led to development of trophoblast organoid and placenta-on-a-chip model, enabling us to study human trophoblast function in context of more physiologically accurate environment. In this review, we will discuss these various model systems, with a focus on human trophoblast, and their ability to help elucidate the key mechanisms underlying placental development and function. This review focuses on model systems of human trophoblast differentiation, including advantages and limitations of stem cell-based culture, trophoblast organoid, and organ-on-a-chip methods and their applications in understanding placental development and disease
Trophoblast lineage-specific differentiation and associated alterations in preeclampsia and fetal growth restriction.
The human placenta is a poorly-understood organ, but one that is critical for proper development and growth of the fetus in-utero. The epithelial cell type that contributes to primary placental functions is called "trophoblast," including two main subtypes, villous and extravillous trophoblast. Cytotrophoblast and syncytiotrophoblast comprise the villous compartment and contribute to gas and nutrient exchange, while extravillous trophoblast invade and remodel the uterine wall and vessels, in order to supply maternal blood to the growing fetus. Abnormal differentiation of trophoblast contributes to placental dysfunction and is associated with complications of pregnancy, including preeclampsia (PE) and fetal growth restriction (FGR). This review describes what is known about the cellular organization of the placenta during both normal development and in the setting of PE/FGR. It also explains known trophoblast lineage-specific markers and pathways regulating their differentiation, and how these are altered in the setting of PE/FGR, focusing on studies which have used human placental tissues. Finally, it also highlights remaining questions and needed resources to advance this field
The role of Sirtuin1-PPARγ axis in placental development and function.
Placental development is important for proper in utero growth and development of the fetus, as well as maternal well-being during pregnancy. Abnormal differentiation of placental epithelial cells, called trophoblast, is at the root of multiple pregnancy complications, including miscarriage, the maternal hypertensive disorder preeclampsia and intrauterine growth restriction. The ligand-activated nuclear receptor, PPARγ, and nutrient sensor, Sirtuin-1, both play a role in numerous pathways important to cell survival and differentiation, metabolism and inflammation. However, each has also been identified as a key player in trophoblast differentiation and placental development. This review details these studies, and also describes how various stressors, including hypoxia and inflammation, alter the expression or activity of PPARγ and Sirtuin-1, thereby contributing to placenta-based pregnancy complications
PPARγ Regulates Trophoblast Proliferation and Promotes Labyrinthine Trilineage Differentiation
BACKGROUND:Abnormal trophoblast differentiation and function is the basis of many placenta-based pregnancy disorders, including pre-eclampsia and fetal growth restriction. PPARgamma, a ligand-activated nuclear receptor, plays essential roles in placental development; null murine embryos die at midgestation due to abnormalities in all placental layers, in particular, small labyrinth and expanded giant cell layer. Previous studies have focused mostly on the role of PPARgamma in trophoblast invasion. Based on the previously reported role of PPARgamma in preadipocyte differentiation, we hypothesized that PPARgamma also plays a pivotal role in trophoblast differentiation. To test this hypothesis, we report derivation of wild-type and PPARgamma-null trophoblast stem (TS) cells. METHODOLOGY/PRINCIPAL FINDINGS:PPARgamma-null TS cells showed defects in both proliferation and differentiation, specifically into labyrinthine trophoblast. Detailed marker analysis and functional studies revealed reduced differentiation of all three labyrinthine lineages, and enhanced giant cell differentiation, particularly the invasive subtypes. In addition, rosiglitazone, a specific PPARgamma agonist, reduced giant cell differentiation, while inducing Gcm1, a key regulator in labyrinth. Finally, reintroducing PPARgamma into null TS cells, using an adenovirus, normalized invasion and partially reversed defective labyrinthine differentiation, as assessed both by morphology and marker analysis. CONCLUSIONS/SIGNIFICANCE:In addition to regulating trophoblast invasion, PPARgamma plays a predominant role in differentiation of labyrinthine trophoblast lineages, which, along with fetal endothelium, form the vascular exchange interface with maternal blood. Elucidating cellular and molecular mechanisms mediating PPARgamma action will help determine if modulating PPARgamma activity, for which clinical pharmacologic agonists already exist, might modify the course of pregnancy disorders associated with placental dysfunction
Recommended from our members
Author Correction: Role of astroglia in Down's syndrome revealed by patient-derived human-induced pluripotent stem cells.
An amendment to this paper has been published and can be accessed via a link at the top of the paper
Recommended from our members
The BAF and PRC2 Complex Subunits Dpf2 and Eed Antagonistically Converge on Tbx3 to Control ESC Differentiation.
BAF complexes are composed of different subunits with varying functional and developmental roles, although many subunits have not been examined in depth. Here we show that the Baf45 subunit Dpf2 maintains pluripotency and ESC differentiation potential. Dpf2 co-occupies enhancers with Oct4, Sox2, p300, and the BAF subunit Brg1, and deleting Dpf2 perturbs ESC self-renewal, induces repression of Tbx3, and impairs mesendodermal differentiation without dramatically altering Brg1 localization. Mesendodermal differentiation can be rescued by restoring Tbx3 expression, whose distal enhancer is positively regulated by Dpf2-dependent H3K27ac maintenance and recruitment of pluripotency TFs and Brg1. In contrast, the PRC2 subunit Eed binds an intragenic Tbx3 enhancer to oppose Dpf2-dependent Tbx3 expression and mesendodermal differentiation. The PRC2 subunit Ezh2 likewise opposes Dpf2-dependent differentiation through a distinct mechanism involving Nanog repression. Together, these findings delineate distinct mechanistic roles for specific BAF and PRC2 subunits during ESC differentiation
- …