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Seminars in Cell & Developmental Biology Nov 2022The placenta is a transient fetal organ that plays a critical role in the health and wellbeing of both the fetus and its mother. Functionally, the placenta sustains the... (Review)
Review
The placenta is a transient fetal organ that plays a critical role in the health and wellbeing of both the fetus and its mother. Functionally, the placenta sustains the growth of the fetus as it facilitates delivery of oxygen and nutrients and removal of waste products. Not surprisingly, defective early placental development is the primary cause of common disorders of pregnancy, including recurrent miscarriage, fetal growth restriction, pre-eclampsia and stillbirth. Adverse pregnancy conditions will also affect the life-long health of the fetus via developmental programming[1]. Despite its critical importance in reproductive success and life-long health, our understanding of placental development is not extensive, largely due to ethical limitations to studying early or chronological placental development, lack of long-term in vitro models, or comparative animal models. In this review, we examine current knowledge of early human placental development, discuss the critical role of the maternal endometrium and of the fetal-maternal dialogue in pregnancy success, and we explore the latest models of trophoblast and endometrial stem cells. In addition, we discuss the role of oxygen in placental formation and function, how nutrient delivery is mediated during the periods of histotrophic nutrition (uptake of uterine secretions) and haemotrophic nutrition (exchange between the maternal and fetal circulations), and how placental endocrine function facilitates fetal growth and development.
Topics: Animals; Female; Fetal Development; Humans; Maternal-Fetal Exchange; Oxygen; Placenta; Placentation; Pregnancy
PubMed: 35393235
DOI: 10.1016/j.semcdb.2022.03.039 -
Cellular and Molecular Life Sciences :... Sep 2019Abnormal placentation is considered as an underlying cause of various pregnancy complications such as miscarriage, preeclampsia and intrauterine growth restriction, the... (Review)
Review
Abnormal placentation is considered as an underlying cause of various pregnancy complications such as miscarriage, preeclampsia and intrauterine growth restriction, the latter increasing the risk for the development of severe disorders in later life such as cardiovascular disease and type 2 diabetes. Despite their importance, the molecular mechanisms governing human placental formation and trophoblast cell lineage specification and differentiation have been poorly unravelled, mostly due to the lack of appropriate cellular model systems. However, over the past few years major progress has been made by establishing self-renewing human trophoblast stem cells and 3-dimensional organoids from human blastocysts and early placental tissues opening the path for detailed molecular investigations. Herein, we summarize the present knowledge about human placental development, its stem cells, progenitors and differentiated cell types in the trophoblast epithelium and the villous core. Anatomy of the early placenta, current model systems, and critical key regulatory factors and signalling cascades governing placentation will be elucidated. In this context, we will discuss the role of the developmental pathways Wingless and Notch, controlling trophoblast stemness/differentiation and formation of invasive trophoblast progenitors, respectively.
Topics: Cardiovascular Diseases; Cell Differentiation; Diabetes Mellitus, Type 2; Female; Humans; Models, Biological; Placenta; Placentation; Pregnancy; Signal Transduction; Trophoblasts
PubMed: 31049600
DOI: 10.1007/s00018-019-03104-6 -
Placenta Jul 2020The placenta is essential for the efficient delivery of nutrients and oxygen from mother to fetus to maintain normal fetal growth. Dysfunctional placental development... (Review)
Review
The placenta is essential for the efficient delivery of nutrients and oxygen from mother to fetus to maintain normal fetal growth. Dysfunctional placental development underpins many pregnancy complications, including fetal growth restriction (FGR) a condition in which the fetus does not reach its growth potential. The FGR placenta is smaller than normal placentae throughout gestation and displays maldevelopment of both the placental villi and the fetal vasculature within these villi. Specialized epithelial cells called trophoblasts exhibit abnormal function and development in FGR placentae. This includes an altered balance between proliferation and apoptotic death, premature cellular senescence, and reduced colonisation of the maternal decidual tissue. Thus, the placenta undergoes aberrant changes at the macroscopic to cellular level in FGR, which can limit exchange capacity and downstream fetal growth. This review aims to compile stereological, in vitro, and imaging data to create a holistic overview of the FGR placenta and its pathophysiology, with a focus on the contribution of trophoblasts.
Topics: Animals; Chorionic Villi; Female; Fetal Growth Retardation; Humans; Infant, Newborn; Infant, Small for Gestational Age; Placenta; Placentation; Pregnancy; Trophoblasts
PubMed: 32421528
DOI: 10.1016/j.placenta.2020.05.003 -
American Journal of Obstetrics and... Feb 2022Preeclampsia is a disease whose characterization has not changed in the 150 years since the cluster of signs associated with the disorder were first described. Although... (Review)
Review
Preeclampsia is a disease whose characterization has not changed in the 150 years since the cluster of signs associated with the disorder were first described. Although our understanding of the pathophysiology of preeclampsia has advanced considerably since then, there is still little consensus regarding the true etiology of preeclampsia. As a consequence, preeclampsia has earned the moniker "disease of theories," predominantly because the underlying biological mechanisms linking clinical epidemiologic findings to observed organ dysfunction in preeclampsia are far from clear. Despite the lack of cohesive evidence, expert consensus favors the hypothesis that preeclampsia is a primary placental disorder. However, there is now emerging evidence that suboptimal maternal cardiovascular performance resulting in uteroplacental hypoperfusion is more likely to be the cause of secondary placental dysfunction in preeclampsia. Preeclampsia and cardiovascular disease share the same risk factors, preexisting cardiovascular disease is the strongest risk factor (chronic hypertension, congenital heart disease) for developing preeclampsia, and there are now abundant data from maternal echocardiography and angiogenic marker studies that cardiovascular dysfunction precedes the development of preeclampsia by several weeks or months. Importantly, cardiovascular signs and symptoms (hypertension, cerebral edema, cardiac dysfunction) predominate in preeclampsia at clinical presentation and persist into the postnatal period with a 30% risk of chronic hypertension in the decade after birth. Placental malperfusion caused by suboptimal maternal cardiovascular performance may lead to preeclampsia, thereby explaining the preponderance of cardiovascular drugs (aspirin, calcium, statins, metformin, and antihypertensives) in preeclampsia prevention strategies. Despite the seriousness of the maternal and fetal consequences, we are still developing sensitive screening, reliable diagnostic, effective therapeutic, or improvement strategies for postpartum maternal cardiovascular legacy in preeclampsia. The latter will only become clear with an acceptance and understanding of the cardiovascular etiology of preeclampsia.
Topics: Cardiovascular Diseases; Female; Humans; Parity; Placenta; Placental Circulation; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Vascular Resistance
PubMed: 33771361
DOI: 10.1016/j.ajog.2020.10.024 -
American Journal of Obstetrics and... Oct 2015Discarded at birth, the placenta is a highly complex and fascinating organ. During the course of a pregnancy, it acts as the lungs, gut, kidneys, and liver of the fetus.... (Review)
Review
Discarded at birth, the placenta is a highly complex and fascinating organ. During the course of a pregnancy, it acts as the lungs, gut, kidneys, and liver of the fetus. The placenta also has major endocrine actions that modulate maternal physiology and metabolism and provides a safe and protective milieu in which the fetus can develop. The human placenta undergoes dramatic transformations in form and function between the first trimester, when organogenesis occurs, and the remainder of pregnancy that reflect evolutionary responses to changing oxygen concentrations in the earth's atmosphere. Recent research indicates a more interactive dialogue between the placenta and the maternal tissues than previously recognized. The endometrial glands provide histotrophic support during the first weeks of pregnancy, and the placenta appears able to stimulate its own development by up-regulating gland activity in response to endocrine signals. Extravillous trophoblast cells migrate from the placenta into the uterine wall, in which they interact with cells of the maternal innate immune system. These interactions have a physiological, rather than a classical immunological, outcome and most probably mediate remodeling of the uterine spiral arteries that supply the placenta. Furthermore, deportation of aggregates of transcriptionally active trophoblast nuclei, and the release of exosomes carrying microribonucleic acids challenge our perceptions of fetal-maternal signaling and where the placental interface actually lies. Here we reconsider definitions of the placenta in the light of these recent advances.
Topics: Animals; Female; Humans; Placenta; Placentation; Pregnancy
PubMed: 26428504
DOI: 10.1016/j.ajog.2015.07.050 -
Cellular and Molecular Life Sciences :... May 2022Correct development of the human placenta and its differentiated epithelial cells, syncytial trophoblasts (STBs) and extravillous trophoblasts (EVTs), is crucial for a... (Review)
Review
Correct development of the human placenta and its differentiated epithelial cells, syncytial trophoblasts (STBs) and extravillous trophoblasts (EVTs), is crucial for a successful pregnancy outcome. STBs develop by cell fusion of mononuclear cytotrophoblasts (CTBs) in placental floating villi, whereas migratory EVTs originate from specialized villi anchoring to the maternal decidua. Defects in trophoblast differentiation have been associated with severe pregnancy disorders such as early-onset preeclampsia and fetal growth restriction. However, the evolutionary pathways underlying normal and adverse placentation are poorly understood. Herein, we discuss Wingless (WNT) and NOTCH signaling, two pathways that play pivotal roles in human placenta and trophoblast development. Whereas WNT is necessary for expansion of trophoblast progenitors and stem cells, NOTCH1 is required for proliferation and survival of EVT precursors. Differentiation of the latter is orchestrated by a switch in NOTCH receptor expression as well as by changes in WNT ligands and their downstream effectors.
Topics: Cell Differentiation; Female; Humans; Placenta; Placentation; Pregnancy; Receptors, Notch; Trophoblasts
PubMed: 35562545
DOI: 10.1007/s00018-022-04285-3 -
Circulation Mar 2023Placental heart development and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor...
BACKGROUND
Placental heart development and embryonic heart development occur in parallel, and these organs have been proposed to exert reciprocal regulation during gestation. Poor placentation has been associated with congenital heart disease, an important cause of infant mortality. However, the mechanisms by which altered placental development can lead to congenital heart disease remain unresolved.
METHODS
In this study, we use an in vivo neutrophil-driven placental inflammation model through antibody depletion of maternal circulating neutrophils at key stages during time-mated murine pregnancy: embryonic days 4.5 and 7.5. Pregnant mice were culled at embryonic day 14.5 to assess placental and embryonic heart development. A combination of flow cytometry, histology, and bulk RNA sequencing was used to assess placental immune cell composition and tissue architecture. We also used flow cytometry and single-cell sequencing to assess embryonic cardiac immune cells at embryonic day 14.5 and histology and gene analyses to investigate embryonic heart structure and development. In some cases, offspring were culled at postnatal days 5 and 28 to assess any postnatal cardiac changes in immune cells, structure, and cardiac function, as measured by echocardiography.
RESULTS
In the present study, we show that neutrophil-driven placental inflammation leads to inadequate placental development and loss of barrier function. Consequently, placental inflammatory monocytes of maternal origin become capable of migration to the embryonic heart and alter the normal composition of resident cardiac macrophages and cardiac tissue structure. This cardiac impairment continues into postnatal life, hindering normal tissue architecture and function. Last, we show that tempering placental inflammation can prevent this fetal cardiac defect and is sufficient to promote normal cardiac function in postnatal life.
CONCLUSIONS
Taken together, these observations provide a mechanistic paradigm whereby neutrophil-driven inflammation in pregnancy can preclude normal embryonic heart development as a direct consequence of poor placental development, which has major implications on cardiac function into adult life.
Topics: Pregnancy; Female; Mice; Animals; Placenta; Placentation; Fetus; Inflammation; Heart Defects, Congenital
PubMed: 36484244
DOI: 10.1161/CIRCULATIONAHA.122.061934 -
Nature Reviews. Endocrinology Sep 2020Pre-eclampsia and fetal growth restriction arise from disorders of placental development and have some shared mechanistic features. Initiation is often rooted in the... (Review)
Review
Pre-eclampsia and fetal growth restriction arise from disorders of placental development and have some shared mechanistic features. Initiation is often rooted in the maldevelopment of a maternal-placental blood supply capable of providing for the growth requirements of the fetus in later pregnancy, without exerting undue stress on maternal body systems. Here, we review normal development of a placental bed with a safe and adequate blood supply and a villous placenta-blood interface from which nutrients and oxygen can be extracted for the growing fetus. We consider disease mechanisms that are intrinsic to the maternal environment, the placenta or the interaction between the two. Systemic signalling from the endocrine placenta targets the maternal endothelium and multiple organs to adjust metabolism for an optimal pregnancy and later lactation. This signalling capacity is skewed when placental damage occurs and can deliver a dangerous pathogenic stimulus. We discuss the placental secretome including glycoproteins, microRNAs and extracellular vesicles as potential biomarkers of disease. Angiomodulatory mediators, currently the only effective biomarkers, are discussed alongside non-invasive imaging approaches to the prediction of disease risk. Identifying the signs of impending pathology early enough to intervene and ameliorate disease in later pregnancy remains a complex and challenging objective.
Topics: Biomarkers; Decidua; Embryonic Development; Endometrium; Female; Fetal Development; Fetal Growth Retardation; Fetus; Humans; Placenta; Placenta Diseases; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Signal Transduction; Trophoblasts
PubMed: 32601352
DOI: 10.1038/s41574-020-0372-6 -
American Journal of Obstetrics and... Feb 2022Physiological transformation with remodeling of the uteroplacental spiral arteries is key to a successful placentation and normal placental function. It is an intricate... (Review)
Review
Physiological transformation with remodeling of the uteroplacental spiral arteries is key to a successful placentation and normal placental function. It is an intricate process that involves, but is not restricted to, complex interactions between maternal decidual immune cells and invasive trophoblasts in the uterine wall. In normal pregnancy, the smooth muscle cells of the arterial tunica media of uteroplacental spiral arteries are replaced by invading trophoblasts and fibrinoid, and the arterial diameter increases 5- to 10-fold. Poor remodeling of the uteroplacental spiral arteries is linked to early-onset preeclampsia and several other major obstetrical syndromes, including fetal growth restriction, placental abruption, and spontaneous preterm premature rupture of membranes. Extravillous endoglandular and endovenous trophoblast invasions have recently been put forth as potential contributors to these syndromes as well. The well-acknowledged disturbed extravillous invasion of maternal spiral arteries in preeclampsia is summarized, as are briefly novel concepts of disturbed extravillous endoglandular and endovenous trophoblast invasions. Acute atherosis is a foam cell lesion of the uteroplacental spiral arteries associated with poor remodeling. It shares some morphologic features with early stages of atherosclerosis, but several molecular differences between these lesions have also recently been revealed. Acute atherosis is most prevalent at the maternal-fetal interface, at the tip of the spiral arteries. The localization of acute atherosis downstream of poorly remodeled arteries suggests that alterations in blood flow may trigger inflammation and foam cell development. Acute atherosis within the decidua basalis is not, however, confined to unremodeled areas of spiral arteries or to hypertensive disorders of pregnancy and may even be present in some clinically uneventful pregnancies. Given that foam cells of atherosclerotic lesions are known to arise from smooth muscle cells or macrophages activated by multiple types of inflammatory stimulation, we have proposed that multiple forms of decidual vascular inflammation may cause acute atherosis, with or without poor remodeling and/or preeclampsia. Furthermore, we propose that acute atherosis may develop at different gestational ages, depending on the type and degree of the inflammatory insult. This review summarizes the current knowledge of spiral artery remodeling defects and acute atherosis in preeclampsia. Some controversies will be presented, including endovascular and interstitial trophoblast invasion depths, the concept of 2-stage trophoblast invasion, and whether the replacement of maternal spiral artery endothelium by fetal endovascular trophoblasts is permanent. We will discuss the role of acute atherosis in the pathophysiology of preeclampsia and short- and long-term health correlates. Finally, we suggest future opportunities for research on this intriguing uteroplacental interface between the mother and fetus.
Topics: Atherosclerosis; Decidua; Female; Humans; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Trophoblasts; Uterine Artery; Vascular Remodeling
PubMed: 32971013
DOI: 10.1016/j.ajog.2020.09.026 -
Cellular and Molecular Life Sciences :... Jun 2022Human pregnancy depends on the proper development of the embryo prior to implantation and the implantation of the embryo into the uterine wall. During the... (Review)
Review
Human pregnancy depends on the proper development of the embryo prior to implantation and the implantation of the embryo into the uterine wall. During the pre-implantation phase, formation of the morula is followed by internalization of blastomeres that differentiate into the pluripotent inner cell mass lineage, while the cells on the surface undergo polarization and differentiate into the trophectoderm of the blastocyst. The trophectoderm mediates apposition and adhesion of the blastocyst to the uterine epithelium. These processes lead to a stable contact between embryonic and maternal tissues, resulting in the formation of a new organ, the placenta. During implantation, the trophectoderm cells start to differentiate and form the basis for multiple specialized trophoblast subpopulations, all of which fulfilling specific key functions in placentation. They either differentiate into polar cells serving typical epithelial functions, or into apolar invasive cells that adapt the uterine wall to progressing pregnancy. The composition of these trophoblast subpopulations is crucial for human placenta development and alterations are suggested to result in placenta-associated pregnancy pathologies. This review article focuses on what is known about very early processes in human reproduction and emphasizes on morphological and functional aspects of early trophoblast differentiation and subpopulations.
Topics: Blastocyst; Cell Differentiation; Embryo Implantation; Female; Humans; Placenta; Placentation; Pregnancy; Trophoblasts
PubMed: 35661923
DOI: 10.1007/s00018-022-04377-0