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Current Opinion in Cell Biology Dec 2020The maintenance of gestational well-being requires the proper development of both the embryo and the placenta. Placental trophoblast cells are the major building blocks... (Review)
Review
The maintenance of gestational well-being requires the proper development of both the embryo and the placenta. Placental trophoblast cells are the major building blocks of the developing placenta. Abnormal trophoblast differentiation underpins placental-based pregnancy complications. However, the mechanisms that govern trophoblast differentiation remain largely unclear. Recent studies shed light on several proteins and regulators that are involved in governing trophoblast differentiation. The advancement of new tools and novel technologies, such as the human trophoblast stem cell culture system, 3D placental organoids and single-cell multi-omics, has brought incredible insights to the field. Here we review the current literature, paying particular attention to articles published between 2017 and 2019 that have promoted our understanding of human trophoblast cell differentiation and its roles in pregnancy and its complications. At the same time, we address challenges and questions arising in the field of human placental development and disease.
Topics: Cell Differentiation; Female; Humans; Organoids; Placenta; Placentation; Pregnancy; Stem Cells; Trophoblasts
PubMed: 32957014
DOI: 10.1016/j.ceb.2020.08.010 -
Nature Protocols Oct 2020The human placenta is essential for successful reproduction. There is great variation in the anatomy and development of the placenta in different species, meaning that...
The human placenta is essential for successful reproduction. There is great variation in the anatomy and development of the placenta in different species, meaning that animal models provide limited information about human placental development and function. Until recently, it has been impossible to isolate trophoblast cells from the human placenta that proliferate in vitro. This has limited our ability to understand pregnancy disorders. Generating an in vitro model that recapitulates the unique features of the human placenta has been challenging. The first in vitro model system of human trophoblast that could be cultured long term and differentiated to syncytiotrophoblast (SCT) and extravillous trophoblast (EVT) was a two-dimensional (2D) culture system of human trophoblast stem cells. Here, we describe a protocol to isolate trophoblast from first-trimester human placentas that can be grown long term in a three-dimensional (3D) organoid culture system. Trophoblast organoids can be established within 2-3 weeks, passaged every 7-10 d, and cultured for over a year. The structural organization of these human trophoblast organoids closely resembles the villous placenta with a layer of cytotrophoblast (VCT) that differentiates into superimposed SCT. Altering the composition of the medium leads to differentiation of the trophoblast organoids into HLA-G+ EVT cells which rapidly migrate and invade through the Matrigel droplet in which they are cultured. Our previous research confirmed that there is similarity between the trophoblast organoids and in vivo placentas in their transcriptomes and ability to produce placental hormones. This organoid culture system provides an experimental model to investigate human placental development and function as well as interactions of trophoblast cells with the local and systemic maternal environment.
Topics: Cell Culture Techniques; Cell Differentiation; Female; Humans; Organoids; Placenta; Pregnancy; Stem Cells; Trophoblasts
PubMed: 32908314
DOI: 10.1038/s41596-020-0381-x -
Advances in Experimental Medicine and... 2011The villous trophoblast of the human placenta is the epithelial cover of the fetal chorionic villi floating in maternal blood. This epithelial cover is organized in two... (Review)
Review
The villous trophoblast of the human placenta is the epithelial cover of the fetal chorionic villi floating in maternal blood. This epithelial cover is organized in two distinct layers, the multinucleated syncytiotrophoblast directly facing maternal blood and a second layer of mononucleated cytotrophoblasts. During pregnancy single cytotrophoblasts continuously fuse with the overlying syncytiotrophoblast to preserve this end-differentiated layer until delivery. Syncytial fusion continuously supplies the syncytiotrophoblast with compounds of fusing cytotrophoblasts such as proteins, nucleic acids and lipids as well as organelles. At the same time the input of cytotrophoblastic components is counterbalanced by a continuous release of apoptotic material from the syncytiotrophoblast into maternal blood. Fusion is an essential step in maintaining the syncytiotrophoblast. Trophoblast fusion was shown to be dependant on and regulated by multiple factors such as fusion proteins, proteases and cytoskeletal proteins as well as cytokines, hormones and transcription factors. In this chapter we focus on factors that may be involved in the fusion process of trophoblast directly or that may prepare the cytotrophoblast to fuse.
Topics: Animals; Caspases; Female; Giant Cells; Humans; Membrane Fusion; Pregnancy; Trophoblasts
PubMed: 21432015
DOI: 10.1007/978-94-007-0763-4_6 -
Histochemistry and Cell Biology Oct 2018Until recently, trophoblast invasion during human placentation was characterized by and restricted to invasion into uterine connective tissues and the uterine spiral... (Review)
Review
Until recently, trophoblast invasion during human placentation was characterized by and restricted to invasion into uterine connective tissues and the uterine spiral arteries. The latter was explained to connect the arteries to the intervillous space of the placenta and to guarantee the blood supply of the mother to the placenta. Today, this picture has dramatically changed. Invasion of endoglandular trophoblast into uterine glands, already starting at the time of implantation, enables histiotrophic nutrition of the embryo prior to perfusion of the placenta with maternal blood. This is followed by invasion of endovenous trophoblasts into uterine veins to guarantee the drainage of fluids from the placenta back into the maternal circulation throughout pregnancy. In addition, invasion of endolymphatic trophoblasts into the lymph vessels of the uterus has been described. Only then, invasion of endoarterial trophoblasts into spiral arteries takes place, enabling hemotrophic nutrition of the fetus starting with the second trimester of pregnancy. This new knowledge paves the way to identify changes that may occur in pathological pregnancies, from tubal pregnancies to recurrent spontaneous abortions.
Topics: Cell Movement; Female; Humans; Pregnancy; Trophoblasts
PubMed: 30046889
DOI: 10.1007/s00418-018-1699-0 -
Methods in Enzymology 2006At the first cell fate decision in mammalian development, the origins of trophoblast and embryonic cell lineages are established as the trophectoderm and the inner cell... (Review)
Review
At the first cell fate decision in mammalian development, the origins of trophoblast and embryonic cell lineages are established as the trophectoderm and the inner cell mass (ICM) in the blastocyst. In the trophoblast cell lineage, a subset of the trophectoderm cells maintains the capacity to proliferate and contribute to the extraembryonic ectoderm, the ectoplacental cone, and the secondary giant cells of the early conceptus after implantation, and finally they produce the entire trophoblastic population in the mature placenta. The stem cell population of the trophectoderm lineage can be isolated and maintained in vitro in the presence of fibroblast growth factor 4, heparin, and a feeder layer of mouse embryonic fibroblast cells. These apparently immortal stem cells in culture are termed trophoblast stem (TS) cells, and exhibit the potential to differentiate into multiple trophoblastic cell types in vitro, as well as in vivo. Even after multiple passages, TS cells retain the ability to participate in the normal development of chimeras and contribute exclusively to the trophoblastic component of the placenta and of the parietal yolk sac. The fate of TS cells is strikingly in contrast to that of embryonic stem cells, which never contribute to these tissues. In this chapter, detailed protocols for the isolation and establishment of TS cell lines from blastocysts and their maintenance are described.
Topics: Animals; Cell Culture Techniques; Embryonic Stem Cells; Humans; Trophoblasts
PubMed: 17141063
DOI: 10.1016/S0076-6879(06)19015-1 -
The International Journal of... Dec 2018The placenta is the first organ to be created during mammalian development. As the main link between the mother and the fetus it has more diverse functions than any... (Review)
Review
The placenta is the first organ to be created during mammalian development. As the main link between the mother and the fetus it has more diverse functions than any other organ, serving as a digestive, excretory, respiratory, endocrine, and immune system. The outer layer of the placenta, the trophoblast, plays a key role in fetal development by orchestrating all these functions. Recent research has associated perturbations of maternal conditions (such as malnutrition, stress or inflammation) with alterations of the trophoblasts' endocrine, transport and metabolic processes. As reviewed here, adaptations to these conditions enable the fetus to survive, but at the cost of permanently changing its physiology and structure. Moreover, these adaptations trigger fetal programming that increases predisposition to various pathological conditions in adult life, typically metabolic, cardiovascular or CNS diseases.
Topics: Animals; Female; Fetal Development; Humans; Maternal-Fetal Exchange; Models, Biological; Placenta; Pregnancy; Prenatal Exposure Delayed Effects; Trophoblasts; Xenobiotics
PubMed: 30266525
DOI: 10.1016/j.biocel.2018.09.016 -
Reproductive Toxicology (Elmsford, N.Y.) Jan 2022During pregnancy, the migration and invasion of extravillous trophoblasts (EVTs) into the maternal uterus is essential for proper development of the placenta and fetus.... (Review)
Review
During pregnancy, the migration and invasion of extravillous trophoblasts (EVTs) into the maternal uterus is essential for proper development of the placenta and fetus. During the first trimester, EVTs engraft and remodel maternal spiral arteries allowing for efficient blood flow and the transfer of essential nutrients and oxygen to the fetus. Aberrant migration of EVTs leading to either shallow or deep invasion into the uterus has been implicated in a number of gestational pathologies including preeclampsia, fetal growth restriction, and placenta accreta spectrum. The migration and invasion of EVTs is well-coordinated to ensure proper placentation. However, recent data point to the ability of xenobiotics to disrupt EVT migration. These xenobiotics include heavy metals, endocrine disrupting chemicals, and organic contaminants and have often been associated with adverse pregnancy outcomes. In most instances, xenobiotics appear to reduce EVT migration; however, there are select examples of enhanced motility after chemical exposure. In this review, we provide an overview of the 1) current experimental approaches used to evaluate EVT migration and invasion in vitro, 2) ability of environmental chemicals and pharmaceuticals to enhance or retard EVT motility, and 3) signaling pathways responsible for altered EVT migration that are sensitive to disruption by xenobiotics.
Topics: Animals; Cell Movement; Drug-Related Side Effects and Adverse Reactions; Environmental Pollutants; Humans; Trophoblasts; Xenobiotics
PubMed: 34838982
DOI: 10.1016/j.reprotox.2021.11.008 -
Reproduction (Cambridge, England) Jul 2020Appropriate human trophoblast lineage specification and differentiation is crucial for the establishment of normal placentation and maintenance of pregnancy. However,... (Review)
Review
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.
Topics: Cell Differentiation; Epithelium; Female; Humans; Maternal-Fetal Exchange; Models, Biological; Placenta; Placentation; Pregnancy; Trophoblasts
PubMed: 32485667
DOI: 10.1530/REP-19-0428 -
Progress in Molecular Biology and... 2017The placenta is a transient organ that plays a critical role in sustaining pregnancy and supporting fetal growth and nutrition. The placental epithelium is comprised of... (Review)
Review
The placenta is a transient organ that plays a critical role in sustaining pregnancy and supporting fetal growth and nutrition. The placental epithelium is comprised of trophoblast cells. Trophoblast cells are the first cell type to differentiate during embryogenesis and ultimately diversify into a heterogeneous population of cells specializing in distinct functions essential for placentation. The emergence of the trophoblast lineage and subsequent specialization into distinct trophoblast sublineages is tightly regulated by transcription factors. This chapter will provide an overview of transcription factors that regulate trophoblast development and function. The chapter is divided into three sections. In the first section, a generalized outline of trophoblast ontogeny and a functional description of different trophoblast sublineages will be provided. In the second section, transcription factors involved in emergence of the trophoblast lineage and maintenance of trophoblast stem cells will be discussed. In the third section, transcription factors implicated in the formation and function of villous and extravillous cytotrophoblast lineages will be described.
Topics: Animals; Cell Lineage; Fetal Blood; Humans; Models, Biological; Transcription Factors; Trophoblasts
PubMed: 28110754
DOI: 10.1016/bs.pmbts.2016.12.003 -
Biotechnology Journal Apr 2013Molecular mechanisms regulating human trophoblast differentiation remain poorly understood due to difficulties in obtaining primary tissues from very early developmental... (Review)
Review
Molecular mechanisms regulating human trophoblast differentiation remain poorly understood due to difficulties in obtaining primary tissues from very early developmental stages in humans. Therefore, the use of human embryonic stem cells (hESCs) as a source for generating trophoblast tissues is of significant interest. Trophoblast-like cells have been obtained through treatment of hESCs with bone morphogenetic protein (BMP) or inhibitors of activin/nodal/transforming growth factor-β signaling, or through protocols involving formation of embryoid bodies (EBs); however, there is controversy over whether hESC-derived cells are indeed analogous to true trophoblasts found in vivo. In this review, we provide an overview of previously described efforts to obtain trophoblasts from hESCs. We also discuss the merits and limitations of hESCs as a source of trophoblast derivatives.
Topics: Animals; Bone Morphogenetic Proteins; Cell Culture Techniques; Cell Differentiation; Embryonic Stem Cells; Humans; Trophoblasts
PubMed: 23325630
DOI: 10.1002/biot.201200203