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Extraembryonic membranes in fish, birds and mammals. The yolk sac dates back to our aquatic ancestors and thus represents the phylogenetically oldest extraembryonic tissue. Amnion, chorion and allantois are inventions of the amniotic egg, which have been subsequently adapted in mammals to support embryonic development inside the uterus. mya million years ago.
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Human embryogenesis is hallmarked by two phases of yolk sac development. The primate hypoblast gives rise to a transient primary yolk sac, which is rapidly superseded by a secondary yolk sac during gastrulation. Moreover, primate embryos form extraembryonic mesoderm prior to gastrulation, in contrast to mouse. The function of the primary yolk sac a...
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... reproduction on land required substantial rearrangements of the aquatic egg, in particular with regard to gas exchange, waste disposal and protection from desiccation 2,3 . To accomplish this challenge, amniotes (the clade of reptiles, birds and mammals) have developed three additional extraembryonic membranes: amnion, chorion, and allantois 3 ( Fig. 1). The evolution of amniotic eggs with large yolk-filled sacs, extensive extraembryonic tissues and less gelatinous shells effectively liberated amniotes from aquatic environments and allowed them to conquer dryer habitats inland. Strikingly, all extraembryonic membranes of the amniotic egg, including the yolk sac, are conserved in ...
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... important consideration is that mammalian viviparity emerged comparatively late and had to be superimposed on the existing structures of the amniotic egg 4 . Thus successful adaptation for in utero development required repurposing of extraembryonic membranes (Fig. 1). As in reptiles and birds, mammalian extraembryonic membranes function as surrogate lung, gut, liver and kidney, long before these organs are formed in the foetus 7 . Mammals establish a cooperative network of extraembryonic tissues consisting of amnion, chorion, yolk sac and allantois (Box 1). The amnion is a transparent membrane, ...
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... AVE formation is associated with local thickening of the visceral endoderm. This can be observed in human embryos as early as CS 5C and 6A 71,72 (Fig. 4). Equally, the anterior-posterior axis is evident in cynomolgus and rhesus embryos at the same stage (ref. 73 and Fig. 12 in ref. 74 ). In cynomolgus, CER1 is initially expressed throughout visceral endoderm and becomes anteriorly restricted within several hours 73 . The cynomolgus AVE secrets DKK1, presumably to locally inhibit strong WNT3A signalling from the overlying trophoblast and amnion 73 . Prior to gastrulation, BMP4 is expressed in the amnion ...
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... the molecular mechanisms of primary haematopoiesis remain poorly understood, it is clear that the intricate vascular system of the yolk sac plays an indispensable role in transporting nutrients throughout the early stages of gestation. As embryonic development progresses towards , ISBN 1455733288, 9781455733286). c The mesothelium exhibits hallmarks of absorption, degradation and re-synthesis, evident by high concentration of LRP2-CUBN-AMN endovesicular complexes in the plasma membrane. Lysosomes contain hydrolytic enzymes, such as the Cathepsins, to mediate the degradation of maternal proteins and other complex molecules in the nutrient-rich exocoelomic cavity. ...
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Dermal fibroblasts isolated from an apparently healthy 50-year-old man were successfully transformed into induced pluripotent stem cells (iPSCs) by using the integration-free CytoTune-iPS Sendai Reprogramming method. The generated iPSC line has been expanded under feeder-free conditions and displayed all hallmarks of a standard pluripotent stem cel...
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... The yolk sac evolved in fish while amniotes additionally developed the amnion, allantois and chorion. Mammals then adapted these four fetal membranes to support their in utero development (Mossman 1937;Ross and Boroviak 2020). Mammalian pregnancy depends on the yolk sac as the early site of maternal-fetal exchange, hematopoeiesis, and biosynthesis (Gulbis et al. 1998;Burton and Jauniaux 2021). ...
... In most marsupials it is the yolk sac that forms the definitive choriovitelline placenta and consists of an avascular bilaminar region ("BOM": bilaminar omphalopleure) and a vascular trilaminar region ("TOM": trilaminar omphalopleure), that in most species are closely apposed to the maternal uterine epithelium until birth (Renfree 1973(Renfree , 2010Freyer et al. 2003;Guernsey et al. 2017). In humans and mice the yolk sac supports the early stages of development before the establishment of the definitive chorioallantoic placenta (Ross and Boroviak 2020;Burton and Jauniaux 2023). ...
Parent-of-origin-specific expression of imprinted genes is critical for successful mammalian growth and development. Insulin, coded by the INS gene, is an important growth factor expressed from the paternal allele in the yolk sac placenta of therian mammals. The tyrosine hydroxylase gene TH encodes an enzyme involved in dopamine synthesis. TH and INS are closely associated in most vertebrates, but the mouse orthologues, Th and Ins2 , are separated by repeated DNA. In mice, Th is expressed from the maternal allele, but the parental origin of expression is not known for any other mammal so it is unclear whether the maternal expression observed in the mouse represents an evolutionary divergence or an ancestral condition. We compared the length of the DNA segment between TH and INS across species and show that separation of these genes occurred in the rodent lineage with an accumulation of repeated DNA. We found that the region containing TH and INS in the tammar wallaby produces at least five distinct RNA transcripts: TH , TH-INS1 , TH-INS2 , lncINS and INS . Using allele-specific expression analysis, we show that the TH/INS locus is expressed from the paternal allele in pre- and postnatal tammar wallaby tissues. Determining the imprinting pattern of TH/INS in other mammals might clarify if paternal expression is the ancestral condition which has been flipped to maternal expression in rodents by the accumulation of repeat sequences.
... [14][15][16] However, owing to limited access to human embryos, applicable approaches, and ethical considerations, knowledge of the regulatory mechanisms controlling human hypoblast lineage segregation is fragmentary. Given that hypoblast derivatives play an integral role in supporting and patterning the primate embryo, 17 understanding how this lineage emerges and progresses is vital. ...
... Their expression increased over time, and after 5 days in FA83X, we detected markers (TTR and CD34) associated with a more matured post-gastrulation-stage yolk sac ( Figure S6A). 17,35,48,50 These results indicated that blastocyst hypoblast cells are not sustained in FA83X but instead progress to post-implantation hypoblast derivative stages. This is in line with our observation that cells gradually lost SOX17 expression after extended culture in FA83X ( Figure S6G). ...
The hypoblast is an essential extraembryonic tissue set aside within the inner cell mass in the blastocyst. Research with human embryos is challenging. Thus, stem cell models that reproduce hypoblast differentiation provide valuable alternatives. We show here that human naive pluripotent stem cell (PSC) to hypoblast
differentiation proceeds via reversion to a transitional ICM-like state from which the hypoblast emerges in concordance with the trajectory in human blastocysts. We identified a window when fibroblast growth factor (FGF) signaling is critical for hypoblast specification. Revisiting FGF signaling in human embryos revealed
that inhibition in the early blastocyst suppresses hypoblast formation. In vitro, the induction of hypoblast is synergistically enhanced by limiting trophectoderm and epiblast fates. This finding revises previous reports and establishes a conservation in lineage specification between mice and humans. Overall, this study demonstrates the utility of human naive PSC-based models in elucidating the mechanistic features of early human embryogenesis.
... Despite the structural differences between the mouse yolk sac and its human equivalent, the definitive secondary yolk sac (Ross and Boroviak, 2020), there is increasing evidence that many metabolic pathways are conserved in the endodermal cell population (Cindrova-Davies et al., 2017, Goh et al., 2023. Despite very different timescales of embryogenesis between the two species, the human yolk sac is present throughout organogenesis, the period when embryos are most susceptible to malformation (Alwan and Chambers, 2015), after which it degenerates and is lost ( Figure 6D). ...
Severe congenital malformations are a frequent cause of premature death and morbidity in children worldwide. Malformations can originate from numerous genetic or non-genetic factors but in most cases the underlying causes are unknown. Genetic disruption of nicotinamide adenine dinucleotide (NAD) de novo synthesis drives the formation of multiple congenital malformations, collectively termed Congenital NAD Deficiency Disorder (CNDD), highlighting the necessity of this pathway during embryogenesis. Previous work in mice shows that NAD deficiency perturbs embryonic development specifically during a critical period when organs are forming. While NAD de novo synthesis is predominantly active in the liver postnatally, the site of activity prior to and during organogenesis is unknown.
Here, we used a mouse model of human CNDD and applied gene expression, enzyme activity and metabolic analyses to assess pathway functionality in the embryonic liver and extraembryonic tissues. We found that the extra-embryonic visceral yolk sac endoderm exclusively performs NAD de novo synthesis during early organogenesis before the embryonic liver takes over this function. Furthermore, under CNDD-inducing conditions, mouse visceral yolk sacs had reduced NAD levels and altered NAD-related metabolic profiles which affected embryo metabolism. Expression of requisite genes for NAD de novo synthesis is conserved in the equivalent yolk sac cell type in humans.
Our findings show that visceral yolk sac-mediated NAD de novo synthesis activity is essential for mouse embryonic development and perturbation of this pathway results in CNDD. Given the functional homology between mouse and human yolk sacs, our data improve the understanding of human congenital malformation causation.
... It is generally thought that hematopoiesis occurs in three transient waves before HSCs are permanently established in the BM throughout the development of mammals [49]. Starting from carnegie stage 7, the first wave of blood cells originated from the blood islands of the yolk sac, producing large and nucleated erythrocytes, macrophages and megakaryocyte [50]. ...
Hematopoietic stem cells (HSCs) are an ideal source for the treatment of many hematological diseases and malignancies, as well as diseases of other systems, because of their two important features, self-renewal and multipotential differentiation, which have the ability to rebuild the blood system and immune system of the body. However, so far, the insufficient number of available HSCs, whether from bone marrow (BM), mobilized peripheral blood or umbilical cord blood, is still the main restricting factor for the clinical application. Therefore, strategies to expand HSCs numbers and maintain HSCs functions through ex vivo culture are urgently required. In this review, we outline the basic biology characteristics of HSCs, and focus on the regulatory factors in BM niche affecting the functions of HSCs. Then, we introduce several representative strategies used for HSCs from these three sources ex vivo expansion associated with BM niche. These findings have deepened our understanding of the mechanisms by which HSCs balance self-renewal and differentiation and provided a theoretical basis for the efficient clinical HSCs expansion.
... An in depth discussion on the formation of the placenta and fetal heart is beyond the scope of this review; interested readers are directed to comprehensive publications on these topics. [12][13][14][15] The key principle of these processes relevant to the present discussion, however, is that placental and cardiac development are temporally linked ( Figure 1). In brief, extraembryonic circulation can be divided into two distinct but overlapping phases: vitelline circulation to the secondary yolk sac, and chorionic circulation to the placenta. ...
The placenta and fetal heart undergo development concurrently during early pregnancy, and, while human studies have reported associations between placental abnormalities and congenital heart disease (CHD), the nature of this relationship remains incompletely understood. Evidence from animal studies suggests a plausible cause and effect connection between placental abnormalities and fetal CHD. Biomechanical models demonstrate the influence of mechanical forces on cardiac development, whereas genetic models highlight the role of confined placental mutations that can cause some forms of CHD. Similar definitive studies in humans are lacking; however, placental pathologies such as maternal and fetal vascular malperfusion and chronic deciduitis are frequently observed in pregnancies complicated by CHD. Moreover, maternal conditions such as diabetes and pre‐eclampsia, which affect placental function, are associated with increased risk of CHD in offspring. Bridging the gap between animal models and human studies is crucial to understanding how placental abnormalities may contribute to human fetal CHD. The next steps will require new methodologies and multidisciplinary approaches combining innovative imaging modalities, comprehensive genomic testing, and histopathology. These studies may eventually lead to preventative strategies for some forms of CHD by targeting placental influences on fetal heart development.
... Despite the fact that the epithelia with polygonal intercellular boundaries are known for several centuries, it is still under discussion how cellular geometry affects mechanical properties of epithelia, processes of cell growth, division and death [1][2][3][4][5]. Moreover, transformation of flat epithelial monolayers into structures with complex geometry during embryonic development can also be connected with some geometrical changes in the tissues [6][7][8][9][10][11]. * Authors to whom any correspondence should be addressed. ...
Most of normal proliferative epithelia of plants and metazoans are topologically invariant and characterized by similar cell distributions according to the number of cell neighbors (DCNs). Here we study peculiarities of these distributions and explain why the DCN obtained from the location of intercellular boundaries and that based on the Voronoi tessellation with nodes located on cell nuclei may differ from each other. As we demonstrate, special microdomains where four or more intercellular boundaries converge are topologically charged. Using this fact, we deduce a new equation describing the topological balance of the DCNs. The developed theory is applied for a series of microphotographs of non-tumoral epithelial cells of the human cervix (HCerEpiC) to improve the image processing near the edges of microphotographs and reveal the topological invariance of the examined monolayers. Special contact microdomains may be present in epithelia of various natures, however, considering the well-known vertex model of epithelium, we show that such contacts are absent in the usual solid-like state of the model and appear only in the liquid-like cancer state. Also, we discuss a possible biological role of special contacts in context of proliferative epithelium dynamics and tissue morphogenesis.
... Yolk sac is the primary source of exchange between the embryo and the mother before placental circulation and during organogenesis. Yolk sac has immunologic, metabolic, nutritive, endocrine, secretory, excretory and hematopoietic functions [3]. Embryonic heart rate is seen after the appearance of foetal node at 7 w by TAS and 6 w by TVS [2,4]. ...
Objective: Yolk sac is the primary source of exchange between the embryo and the mother before placental circulation and during organogenesis. Yolk sac has immunologic, metabolic, nutritive, endocrine, secretory, excretory and hematopoietic functions. Embryonic heart rate is seen after the appearance of foetal node at 7 w by TAS and 6 w by TVS. Studies have been conducted to establish the importance of yolk sac and EHR in pregnancy outcome. The prognostic significance of the yolk sac for the pregnancy outcome has been assessed with TVS. To measure yolk sac diameter and embryonic heart rate in early pregnancy (less than 10 weeks), to correlate yolk sac measurement and embryonic heart rate individually as prognostic factors for first trimester outcome and to evaluate the measurements in combination as a prognostic marker of first trimester pregnancy outcome. In view of this, the present study was undertaken. Methods: 108 patients attending OPD of Kempe Gowda institute of Medical Sciences Hospital, between 6 to 9 w of gestation, were evaluated with transvaginal sonography and measurements such as CRL, MSD and YSD were taken. Results: The mean age of the study population was 25 y and 88 % of the study population belonged to 20-30 y. 55.6 % of the study population were primigravida. Incidence of abnormal pregnancy outcome was 18.5%. The probability of abnormal outcome increased with the increase in gravidity of the patient (P= 0.890). There was a significant positive comparison of CRL (P= 0.223), GS (P= 0.251) and YSD (P= 0.016). Yolk sac diameter in the first trimester significantly correlates with the pregnancy outcome. An enlarged yolk sac is associated with an increased risk of preterm delivery. Our study influences the pregnancy outcome by the Embryonic heart rate. Foetal bradycardia is an impending sign of foetal death due to chromosomal abnormalities (Trisomy 18), foetal tachycardia featuring Trisomy 21. Conclusion: Yolk sac diameter and embryonic heart rate in the first trimester significantly correlates with the first trimester pregnancy outcome. Thus, the present study indicates that the yolk sac size and the embryonic heart rate is a reliable, beneficial and cost-effective in predicting first-trimester pregnancy outcome. The measurement of the secondary yolk sac diameter between 5th to 9th week of gestation can be used as a valuable tool to predict early pregnancy outcome.
... Gene set variation analysis (GSVA) demonstrated that our bDE like cells bore a higher similarity to the embryo DE identity while bVE/ YSE and bAVE were more similar to the embryo extraembryonic identities (Fig. 5f). In addition, we found evidence of secreted CER1 proteins in the extracellular regions of GATA4+ cell clusters (Fig. 5g), suggesting that these cells may potentially be recapitulating the role of AVE cells as a signaling center to counteract BMP signaling 53 . In view of extraembryonic tissue development, we found both trophoblast descendants, cytotrophoblasts (bCTBs) and syncytiotrophoblasts (bSTBs), and amnion-like cells (bAM) present in our UMAP analysis ( Fig. 5c and Supplementary Fig. 6c). ...
Human naïve pluripotent stem cells (hnPSCs) can generate integrated models of blastocysts termed blastoids upon switch to inductive medium. However, the underlying mechanisms remain obscure. Here we report that self-renewing hnPSCs spontaneously and efficiently give rise to blastoids upon three dimensional (3D) suspension culture. The spontaneous blastoids mimic early stage human blastocysts in terms of structure, size, and transcriptome characteristics and are capable of progressing to post-implantation stages. This property is conferred by the glycogen synthase kinase-3 (GSK3) signalling inhibitor IM-12 present in 5iLAF self-renewing medium. IM-12 upregulates oxidative phosphorylation-associated genes that underly the capacity of hnPSCs to generate blastoids spontaneously. Starting from day one of self-organization, hnPSCs at the boundary of all 3D aggregates dedifferentiate into E5 embryo-like intermediates. Intermediates co-express SOX2/OCT4 and GATA6 and by day 3 specify trophoblast fate, which coincides with cavity and blastoid formation. In summary, spontaneous blastoid formation results from 3D culture triggering dedifferentiation of hnPSCs into earlier embryo-like intermediates which are then competent to segregate blastocyst fates.
... The yolk sac is involved in gastrointestinal tract formation, protein synthesis, stem cell production, and hematopoiesis 9-12 ; for example, it is the origin of macrophage subtypes with high plasticity for epigenetic programming 13 . Through surface diffusion and transport proteins, the yolk sac membrane also facilitates gas exchange and provides nutrients until the placenta is sufficiently developed [9][10][11][12]14 . ...
... capture such effects. Animal studies have also provided some evidence supporting the effect of environmental factors, such as temperature, nutrition, and noise, on the yolk sac [28][29][30][31] , but yolk sac development and implantation mechanisms vary among species 5,10,11 . Nevertheless, the findings of the present study support the concept of the compensatory enlargement of the yolk sac surface to ensure adequate nutritional support for embryonic growth 15 . ...
... Nevertheless, the underlying mechanisms may be similar because they both occur within the same organ, the uterus, with the same supplying vasculature, myometrium, and endometrium that includes glands surrounded by vessels. Therefore, it is plausible that fluctuations capable of influencing placental development may also influence histotrophic nutrition at earlier stages of pregnancy via the uterine glands and vasculature 10,11 . Furthermore, sex steroid levels, which are associated with physical activity in women 45 , are widely recognized to influence both the menstrual cycle and the timing of ovulation, as well as the composition of the endometrium and its glands. ...
This longitudinal study investigated the impact of actigraphy-measured maternal physical activity on yolk sac size during early development. The yolk sac, a transient extraembryonic organ, plays a crucial role in embryonic development and is involved in metabolism, nutrition, growth, and hematopoiesis. Prospectively collected data from 190 healthy women indicated that their total daily physical activity, including both light and moderate-vigorous activity, was associated with yolk sac growth dynamics depending on embryonic sex and gestational age. Higher preconception maternal physical activity was linked to a larger yolk sac at 7 weeks (95% CI [0.02–0.13 mm]) and a smaller yolk sac at 10 weeks’ gestation (95% CI [− 0.18 to − 0.00]) in male embryos; in female embryos, the yolk sac size was increased at 10 weeks’ gestation (95% CI [0.06–0.26]) and was, on average, 24% larger than that in male embryos (95% CI [0.12–0.38]). Considering the pattern of other maternal effects on yolk sac size—e.g., body composition and sleep duration—we suggest that physiological yolk sac adaptations occur in short, sex-specific time windows and can be influenced by various maternal factors.
... This suggests that in primates the timing of maturation of these extra-embryonic tissues has diverged from the trunk of mammals. Interestingly, both tissues that appear to mature faster in humans, the ExM and yolk-sac endoderm, are involved in the formation of the blood island and patterning of early blood progenitors [55][56][57][58]. The presence of advanced blood progenitors in the CS7 human embryo was also noted by Tyser et al. [43], it may be that the enhanced maturation of these extra-embryonic tissues could not occur without the 'knock-on' effect of earlier blood maturation. ...
Gastrulation represents a pivotal phase of development and aberrations during this period can have major consequences, from minor anatomical deviations to severe congenital defects. Animal models are used to study gastrulation, however, there is considerable morphological and molecular diversity of gastrula across mammalian species. Here, we provide an overview of the latest research on interspecies developmental control across mammals. This includes single-cell atlases of several mammalian gastrula which have enabled comparisons of the temporal and molecular dynamics of differentiation. These studies highlight conserved cell differentiation regulators and both absolute and relative differences in differentiation dynamics between species. Recent advances in in vitro culture techniques have facilitated the derivation, maintenance and differentiation of cell lines from a range of species and the creation of multi-species models of gastrulation. Gastruloids are three-dimensional aggregates capable of self-organising and recapitulating aspects of gastrulation. Such models enable species comparisons outside the confines of the embryo. We highlight recent in vitro evidence that differentiation processes such as somitogenesis and neuronal maturation scale with known in vivo differences in developmental tempo across species. This scaling is likely due to intrinsic differences in cell biochemistry. We also highlight several studies which provide examples of cell differentiation dynamics being influenced by extrinsic factors, including culture conditions, chimeric co-culture, and xenotransplantation. These collective studies underscore the complexity of gastrulation across species, highlighting the necessity of additional datasets and studies to decipher the intricate balance between intrinsic cellular programs and extrinsic signals in shaping embryogenesis.
