The functional roles of protein glycosylation in human maternal-fetal crosstalk.

BACKGROUND: The establishment of maternal-fetal crosstalk is vital to a successful pregnancy. Glycosylation is a post-translational modification in which glycans (monosaccharide chains) are attached to an organic molecule. Glycans are involved in many physiological and pathological processes. Human endometrial epithelium, endometrial gland secretions, decidual immune cells, and trophoblasts are highly enriched with glycoconjugates and glycan-binding molecules important for a healthy pregnancy. Aberrant glycosylation in the placenta and uterus has been linked to repeated implantation failure and various pregnancy complications, but there is no recent review summarizing the functional roles of glycosylation at the maternal-fetal interface and their associations with pathological processes. OBJECTIVE AND RATIONALE: This review aims to summarize recent findings on glycosylation, glycosyltransferases, and glycan-binding receptors at the maternal-fetal interface, and their involvement in regulating the biology and pathological conditions associated with endometrial receptivity, placentation and maternal-fetal immunotolerance. Current knowledge limitations and future insights into the study of glycobiology in reproduction are discussed. SEARCH METHODS: A comprehensive PubMed search was conducted using the following keywords: glycosylation, glycosyltransferases, glycan-binding proteins, endometrium, trophoblasts, maternal-fetal immunotolerance, siglec, selectin, galectin, repeated implantation failure, early pregnancy loss, recurrent pregnancy loss, preeclampsia, and fetal growth restriction. Relevant reports published between 1980 and 2023 and studies related to these reports were retrieved and reviewed. Only publications written in English were included. OUTCOMES: The application of ultrasensitive mass spectrometry tools and lectin-based glycan profiling has enabled characterization of glycans present at the maternal-fetal interface and in maternal serum. The endometrial luminal epithelium is covered with highly glycosylated mucin that regulates blastocyst adhesion during implantation. In the placenta, fucose and sialic acid residues are abundantly presented on the villous membrane and are essential for proper placentation and establishment of maternal-fetal immunotolerance. Glycan-binding receptors, including selectins, sialic-acid-binding immunoglobulin-like lectins (siglecs) and galectins, also modulate implantation, trophoblast functions and maternal-fetal immunotolerance. Aberrant glycosylation is associated with repeated implantation failure, early pregnancy loss and various pregnancy complications. The current limitation in the field is that most glycobiological research relies on association studies, with few studies revealing the specific functions of glycans. Technological advancements in analytic, synthetic and functional glycobiology have laid the groundwork for further exploration of glycans in reproductive biology under both physiological and pathological conditions. WIDER IMPLICATIONS: A deep understanding of the functions of glycan structures would provide insights into the molecular mechanisms underlying their involvement in the physiological and pathological regulation of early pregnancy. Glycans may also potentially serve as novel early predictive markers and therapeutic targets for repeated implantation failure, pregnancy loss, and other pregnancy complications.

Ambient air pollution and adverse birth outcomes: A review of underlying mechanisms.

Epidemiological data provide varying degrees of evidence for associations between prenatal exposure to ambient air pollutants and adverse birth outcomes (suboptimal measures of fetal growth, preterm birth and stillbirth). To assess further certainty of effects, this review examines the experimental literature base to identify mechanisms by which air pollution (particulate matter, nitrogen dioxide and ozone) could cause adverse effects on the developing fetus. It likely that this environmental insult impacts multiple biological pathways important for sustaining a healthy pregnancy, depending upon the composition of the pollutant mixture and the exposure window owing to changes in physiologic maturity of the placenta, its circulations and the fetus as pregnancy ensues. The current body of evidence indicates that the placenta is a target tissue, impacted by a variety of critical processes including nitrosative/oxidative stress, inflammation, endocrine disruption, epigenetic changes, as well as vascular dysregulation of the maternal-fetal unit. All of the above can disturb placental function and, as a consequence, could contribute to compromised fetal growth as well increasing the risk of stillbirth. Furthermore, given that there is often an increased inflammatory response associated with preterm labour, inflammation is a plausible mechanism mediating the effects of air pollution on premature delivery. In the light of increased urbanisation and an ever-changing climate, both of which increase ambient air pollution and negatively affect vulnerable populations such as pregnant individuals, it is hoped that the collective evidence may contribute to decisions taken to strengthen air quality policies, reductions in exposure to air pollution and subsequent improvements in the health of those not yet born.

Genomic Selection Signals in Andean Highlanders Reveal Adaptive Placental Metabolic Phenotypes That Are Disrupted in Preeclampsia.

BACKGROUND: The chronic hypoxia of high-altitude residence poses challenges for tissue oxygen supply and metabolism. Exposure to high altitude during pregnancy increases the incidence of hypertensive disorders of pregnancy and fetal growth restriction and alters placental metabolism. High-altitude ancestry protects against altitude-associated fetal growth restriction, indicating hypoxia tolerance that is genetic in nature. Yet, not all babies are protected and placental pathologies associated with fetal growth restriction occur in some Andean highlanders. METHODS: We examined placental metabolic function in 79 Andeans (18-45 years; 39 preeclamptic and 40 normotensive) living in La Paz, Bolivia (3600-4100 m) delivered by unlabored Cesarean section. Using a selection-nominated approach, we examined links between putatively adaptive genetic variation and phenotypes related to oxygen delivery or placental metabolism. RESULTS: Mitochondrial oxidative capacity was associated with fetal oxygen delivery in normotensive but not preeclamptic placenta and was also suppressed in term preeclamptic pregnancy. Maternal haplotypes in or within 200 kb of selection-nominated genes were associated with lower placental mitochondrial respiratory capacity (PTPRD [protein tyrosine phosphatase receptor-δ]), lower maternal plasma erythropoietin (CPT2 [carnitine palmitoyl transferase 2], proopiomelanocortin, and DNMT3 [DNA methyltransferase 3]), and lower VEGF (vascular endothelial growth factor) in umbilical venous plasma (TBX5 [T-box transcription factor 5]). A fetal haplotype within 200 kb of CPT2 was associated with increased placental mitochondrial complex II capacity, placental nitrotyrosine, and GLUT4 (glucose transporter type 4) protein expression. CONCLUSIONS: Our findings reveal novel associations between putatively adaptive gene regions and phenotypes linked to oxygen delivery and placental metabolic function in highland Andeans, suggesting that such effects may be of genetic origin. Our findings also demonstrate maladaptive metabolic mechanisms in the context of preeclampsia, including dysregulation of placental oxygen consumption.

Protocol for culturing the endocrine junctional zone of the mouse placenta in serum-free medium.

The lack of a suitable explant culture system restricts the study of factors secreted by the mouse placenta into maternal circulation. Here, we present a protocol for culturing the endocrine junctional zone of the mouse placenta, free from the decidua and labyrinthine layers in serum-free medium. We describe steps for dissecting and separating layers, dicing tissue, and culture setup. We then detail medium processing for downstream analysis. This model allows the investigation of placental signals that may regulate maternal physiology. For complete details on the use and execution of this protocol, please refer to Yung et al. (2023).1.

The human placenta: new perspectives on its formation and function during early pregnancy.

The placenta has evolved to support the development of the embryo and fetus during the different intrauterine periods of life. By necessity, its development must precede that of the embryo. There is now evidence that during embryogenesis and organogenesis, the development of the human placenta is supported by histotrophic nutrition secreted from endometrial glands rather than maternal blood. These secretions provide a plentiful supply of glucose, lipids, glycoproteins and growth factors that stimulate rapid proliferation and differentiation of the villous trophoblast. Furthermore, evidence from endometrial gland organoids indicates that expression and secretion of these products are upregulated following sequential exposure to oestrogen, progesterone and trophoblastic and decidual hormones, in particular prolactin. Hence, a feed-forward signalling dialogue is proposed among the trophoblast, decidua and glands that enables the placenta to stimulate its own development, independent of that of the embryo. Many common complications of pregnancy represent a spectrum of disorders associated with deficient trophoblast proliferation. Increasing evidence suggests that this spectrum is mirrored by one of impaired decidualization, potentially compromising histotroph secretion through diminished prolactin secretion and reduced gland function. Optimizing endometrial wellbeing prior to conception may therefore help to prevent common pregnancy complications, such as miscarriage, growth restriction and pre-eclampsia.

Oxidized ß-Carotene Is a Novel Phytochemical Immune Modulator That Supports Animal Health and Performance for Antibiotic-Free Production.

Oxidized ß-carotene (OxBC), a phytochemical that occurs naturally in plants, is formed by the spontaneous reaction of ß-carotene with ambient oxygen. Synthetic OxBC, obtained by full oxidation of ß-carotene with air, shows considerable promise as an in-feed antimicrobial alternative additive that enhances health and performance in livestock. OxBC is predominantly composed of ß-carotene-oxygen copolymers that have beneficial immune-modulating effects that occur within the innate immune system by priming it to face microbial challenges and by mitigating the inflammatory response. OxBC does not have any direct anti-bacterial activity. Further, unlike traditional immune stimulants, OxBC modulates but does not stimulate and utilize the animal's energy stores unless directly stress-challenged. These immune effects occur by mechanisms distinct from the provitamin A or antioxidant pathways commonly proposed as explanations for ß-carotene's actions. Trials in poultry, swine, and dairy cows with low parts-per-million in-feed OxBC supplementation have shown performance benefits over and above those of feeds containing regular vitamin and mineral premixes. Through its ability to enhance immune function, health, and performance, OxBC has demonstrated utility not only as a viable alternative to in-feed antimicrobials but also in its ability to provide tangible health and performance benefits in applications where antimicrobial usage is precluded.

Perturbation of placental protein glycosylation by endoplasmic reticulum stress promotes maladaptation of maternal hepatic glucose metabolism.

Placental hormones orchestrate maternal metabolic adaptations to support pregnancy. We hypothesized that placental ER stress, which characterizes early-onset pre-eclampsia (ePE), compromises glycosylation, reducing hormone bioactivity and these maladaptations predispose the mother to metabolic disease in later life. We demonstrate ER stress reduces the complexity and sialylation of trophoblast protein N-glycosylation, while aberrant glycosylation of vascular endothelial growth factor reduced its bioactivity. ER stress alters the expression of 66 of the 146 genes annotated with "protein glycosylation" and reduces the expression of sialyltransferases. Using mouse placental explants, we show ER stress promotes the secretion of mis-glycosylated glycoproteins. Pregnant mice carrying placentas with junctional zone-specific ER stress have reduced blood glucose, anomalous hepatic glucose metabolism, increased cellular stress and elevated DNA methyltransferase 3A. Using pregnancy-specific glycoproteins as a readout, we also demonstrate aberrant glycosylation of placental proteins in women with ePE, thus providing a mechanistic link between ePE and subsequent maternal metabolic disorders.

Placental F4-Neuroprostanes and F2-Isoprostanes are altered in gestational diabetes mellitus and maternal obesity.

We investigated whether gestational diabetes mellitus (GDM) associated with maternal obesity modifies the placental profile of F4-Neuroprostanes and F2-Isoprostanes, metabolites of non-enzymatic oxidation of docosahexaenoic acid (DHA) and arachidonic acid (AA), respectively. Twenty-five placental samples were divided into lean (n=11), obesity (n=7) and overweight/obesity+GDM (n=7) groups. F4-Neuroprostanes and F2-Isoprostanes were higher in obesity compared to lean controls, but reduced to levels similar to lean women when obesity is further complicated with GDM. Lower content of F2-Isoprostanes suggests adaptive placental responses in GDM attenuating oxidative stress. However, low levels of placental F4-Neuroprostanes may indicate impaired DHA metabolism in GDM, affecting fetal development and offspring health. These results were not related to differences in placental content of DHA, AA and polyunsaturated fatty acids status nor to maternal diet or gestational weight gain. Placental DHA and AA metabolism differs in obesity and GDM, highlighting the importance of investigating the signalling roles of F4-Neuroprostanes and F2-Isoprostanes in the human term placenta.

Sphingolipids and acylcarnitines are altered in placentas from women with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy and a severe threat to pregnant people and offspring health. The molecular origins of GDM, and in particular the placental responses, are not fully known. The present study aimed to perform a comprehensive characterisation of the lipid species in placentas from pregnancies complicated with GDM using high-resolution MS lipidomics, with a particular focus on sphingolipids and acylcarnitines in a semi-targeted approach. The results indicated that despite no major disruption in lipid metabolism, placentas from GDM pregnancies showed significant alterations in sphingolipids, mostly lower abundance of total ceramides. Additionally, very long-chain ceramides and sphingomyelins with twenty-four carbons were lower, and glucosylceramides with sixteen carbons were higher in placentas from GDM pregnancies. Semi-targeted lipidomics revealed the strong impact of GDM on the placental acylcarnitine profile, particularly lower contents of medium and long-chain fatty-acyl carnitine species. The lower contents of sphingolipids may affect the secretory function of the placenta, and lower contents of long-chain fatty acylcarnitines is suggestive of mitochondrial dysfunction. These alterations in placental lipid metabolism may have consequences for fetal growth and development.

Effect of Oxidized ß-Carotene on Swine Growth Performance under Commercial Production Conditions in Vietnam.

The effects of oxidized ß-carotene (OxBC) were determined upon the growth performance of swine through their full growth cycle under commercial production conditions in Vietnam. Five hundred 28-day-old-weaned barrows and gilts were used in a 140-day complete wean-to-finish feeding trial. Animals were randomized by weight, and each pen contained 20 pigs with the same ratio of barrows to gilts. There were five dietary treatment groups with five replicate pens per treatment: Control basal diet, no antibiotics or OxBC; Basal diet with antibiotics; no OxBC; Basal diet supplemented with 2, 4, or 8 mg OxBC/kg of diet, no antibiotics. Growth performance parameters were calculated for each production stage (Starter: Days 1−28, Grower: Days 29−84, Finisher: Days 85−140) and for the overall study (Days 1−140). OxBC and antibiotics each improved growth rate, feed efficiency, and body weight compared to the unsupplemented control (p < 0.001). Animals receiving 4 and 8 mg/kg OxBC performed better than animals on antibiotics (p < 0.001). In Starter pigs, OxBC reduced the occurrence of diarrhea dose-dependently (2, 4, and 8 mg/kg) and more so than did antibiotics (p < 0.001). These findings support the concept that oxidized ß-carotene can facilitate swine growth and health in the absence of in-feed antibiotics.

Elevated homocysteine activates unfolded protein responses and causes aberrant trophoblast differentiation and mouse blastocyst development.

Hyperhomocysteinemia may arise from folate/vitamin B12 deficiency, genetic polymorphisms, kidney disease, or hypothyroidism. It is associated with an increased risk of early pregnancy loss and placenta-related complications of pregnancy, including pre-eclampsia and fetal growth restriction. While the majority of studies of hyperhomocysteinemia focus on epigenetic changes secondary to metabolic disruption, the effects of homocysteine toxicity on placental development remain unexplored. Here, we investigated the influence of hyperhomocysteinemia on early blastocyst development and trophoblast differentiation. Exposure of cultured blastocysts to high homocysteine levels reduces cell number in the trophectoderm layer, most likely through increased apoptosis. Homocysteine also promotes differentiation of a trophoblast stem cell line. Both effects diminish the stem cell pool, and are mediated in an endoplasmic reticulum (ER) unfolded protein response (UPRER )-dependent manner. Targeted alleviation of UPRER may therefore provide a new therapeutic intervention to improve pregnancy outcome in women with hyperhomocysteinemia.

Safety and uptake of fully oxidized ß-carotene.

Spontaneous oxidation of ß-carotene yields a polymer-rich product (OxBC) together with minor amounts of many apocarotenoids. OxBC's activity extends ß-carotene's benefits beyond vitamin A, finding utility in supporting health in livestock, pets, and humans. Although the naturally occurring form of OxBC is consumed in foods and feeds, a direct demonstration of synthetic OxBC's safety provides additional support for its usage. A toxicological study in rats showed a maximum tolerated single oral dose of 5000 mg/kg, an LD50 of more than 10,000 mg/kg, and a NOAEL of 1875 mg/kg body weight. A repeat-dose 90-day oral toxicity study showed no adverse physiological or pathological effects. A study of OxBC uptake by mice over 2-5 days showed OxBC already was naturally present. The highest levels were in liver, lung, and hamstring. Dosing did not increase levels in liver, kidney, lung, and muscle. Increases occurred in urine, intestinal content, plasma, feces, spleen, and cecum with preferential elimination of polymer, consistent with processing of OxBC. Compared to the 4:1 polymer: apocarotenoid ratio of OxBC, polymer was enriched in liver and spleen and depleted in lung, kidney, hamstring, and abdominal muscle. The apparent control of OxBC in major tissues further supports its safety.

Reprint of: Is Vitamin E the Only Lipid-Soluble, Chain-Breaking Antioxidant in Human Blood Plasma and Erythrocyte Membranes?

The concentrations of lipid-soluble, chain-breaking antioxidants in human plasma and in erythrocyte ghosts have been determined for the first time by an inhibited autoxidation method. The results are very similar to the concentrations of vitamin E measured for the same blood components by the HPLC method. It is concluded that vitamin E, which is largely present as α-tocopherol, is the only significant lipid-soluble, chain-breaking type of antioxidant present in human blood. The concentration of vitamin E in the plasma lipids divided by the concentration of vitamin E in the ghost membrane lipids is approximately a constant despite the large differences in vitamin E-intake and in plasma lipid concentrations in different individuals. Vitamin E/lipid ratios for plasma and ghosts were larger for subjects taking a supplement of α-to- copherol acetate of 100 IU per week, compared to nonsupplemented subjects (based on data from a limited number of subjects). A larger supplement of 2800 IU per week did not significantly increase the vitamin E/lipid ratios.

Chronic Hypoxia in Ovine Pregnancy Recapitulates Physiological and Molecular Markers of Preeclampsia in the Mother, Placenta, and Offspring.

BACKGROUND: Preeclampsia continues to be a prevalent pregnancy complication and underlying mechanisms remain controversial. A common feature of preeclampsia is utero-placenta hypoxia. In contrast to the impact of hypoxia on the placenta and fetus, comparatively little is known about the maternal physiology. METHODS: We adopted an integrative approach to investigate the inter-relationship between chronic hypoxia during pregnancy with maternal, placental, and fetal outcomes, common in preeclampsia. We exploited a novel technique using isobaric hypoxic chambers and in vivo continuous cardiovascular recording technology for measurement of blood pressure in sheep and studied the placental stress in response to hypoxia at cellular and subcellular levels. RESULTS: Chronic hypoxia in ovine pregnancy promoted fetal growth restriction (FGR) with evidence of fetal brain-sparing, increased placental hypoxia-mediated oxidative damage, and activated placental stress response pathways. These changes were linked with dilation of the placental endoplasmic reticulum (ER) cisternae and increased placental expression of the antiangiogenic factors sFlt-1 (soluble fms-like tyrosine kinase 1) and sEng (soluble endoglin), combined with a shift towards an angiogenic imbalance in the maternal circulation. Chronic hypoxia further led to an increase in uteroplacental vascular resistance and the fall in maternal blood pressure with advancing gestation measured in normoxic pregnancy did not occur in hypoxic pregnancy. CONCLUSIONS: Therefore, we show in an ovine model of sea-level adverse pregnancy that chronic hypoxia recapitulates physiological and molecular features of preeclampsia in the mother, placenta, and offspring.

New insights into the etiopathology of placenta accreta spectrum.

Placenta accreta has been described as a spectrum of abnormal attachment of villous tissue to the uterine wall, ranging from superficial attachment to the inner myometrium without interposing decidua to transmural invasion through the entire uterine wall and beyond. These descriptions have prevailed for more than 50 years and form the basis for the diagnosis and grading of accreta placentation. Accreta placentation is essentially the consequence of uterine remodeling after surgery, primarily after cesarean delivery. Large cesarean scar defects in the lower uterine segment are associated with failure of normal decidualization and loss of the subdecidual myometrium. These changes allow the placental anchoring villi to implant, and extravillous trophoblast cells to migrate, close to the serosal surface of the uterus. These microscopic features are central to the misconception that the accreta placental villous tissue is excessively invasive and have led to much confusion and heterogeneity in clinical data. Progressive recruitment of large arteries in the uterine wall, that is, helicine, arcuate, and/or radial arteries, results in high-velocity maternal blood entering the intervillous space from the first trimester of pregnancy and subsequent formation of placental lacunae. Recently, guided sampling of accreta areas at delivery has enabled accurate correlation of prenatal imaging data with intraoperative features and histopathologic findings. In more than 70% of samples, there were thick fibrinoid depositions between the tip of most anchoring villi and the underlying uterine wall and around all deeply implanted villi. The distortion of the uteroplacental interface by these dense depositions and the loss of the normal plane of separation are the main factors leading to abnormal placental attachment. These data challenged the classical concept that placenta accreta is simply owing to villous tissue sitting atop the superficial myometrium without interposed decidua. Moreover, there is no evidence in accreta placentation that the extravillous trophoblast is abnormally invasive or that villous tissue can cross the uterine serosa into the pelvis. It is the size of the scar defect, the amount of placental tissue developing inside the scar, and the residual myometrial thickness in the scar area that determine the distance between the placental basal plate and the uterine serosa and thus the risk of accreta placentation.

Failure of placental detachment in accreta placentation is associated with excessive fibrinoid deposition at the utero-placental interface.

BACKGROUND: The main histopathologic diagnostic criteria for the diagnosis of placenta accreta for more than 80 years has been the finding of a direct attachment of the villous tissue to the superficial myometrium or adjacent to myometrial fibers without interposing decidua. There have been very few detailed histopathologic studies in pregnancies complicated by placenta accreta spectrum disorders and our understanding of the pathophysiology of the condition remains limited. OBJECTIVE: To prospectively evaluate the microscopic changes used in grading and to identify changes that might explain the abnormal placental tissue attachment. STUDY DESIGN: A total of 40 consecutive cesarean delivery hysterectomy specimens for placenta previa accreta at 32 to 37 weeks of gestation with at least 1 histologic slide showing deeply implanted villi were analyzed. Prenatal ultrasound examination included placental location, myometrial thickness, subplacental vascularity and lacunae. Macroscopic changes of the lower segment were recorded during surgery and areas of abnormal placental adherence were sampled for histology. In addition, 7 hysterectomy specimens with placenta in-situ from the Boyd Collection at 20.5 to 32.5 weeks were used as controls. RESULTS: All 40 patients had a history of at least 2 previous cesarean deliveries and presented with a mainly anterior placenta previa. Of note, 37 (92.5%) cases presented with increased subplacental vascularity, 31 (77.5%) cases with myometrial thinning and all with lacunae. Furthermore, 20 (50%) cases presented with subplacental hypervascularity, lacunae score of >3, and lacunae feeder vessels. Intraoperative findings included anterior lower segment wall increased vascularization in 36 (90.0%) cases and extended area of dehiscence in 18 (45.0%) cases. Immediate gross examination of hysterectomy specimens showed an abnormally attached areas involving up to 30% of the basal plate, starting at <2 cm from the dehiscence area in all cases. Histologic examination found deeply implanted villi in 86 (53.8%) samples with only 17 (10.6%) samples presenting with villous tissue reaching at least half the uterine wall thickness. There were no villi crossing the entire thickness of the uterine wall. There was microscopic evidence of myometrial scarification in all cases. Dense fibrinoid deposits, 0.5 to 2 mm thick, were found at the utero-placental interface in 119 (74.4%) of the 160 samples between the anchoring villi and the underlying uterine wall at the accreta areas and around all deeply implanted villi. In the control group, the Nitabuch stria and basal plate became discontinuous with advancing gestation and there was no evidence of fibrinoid deposition at these sites. CONCLUSION: Samples from accreta areas at delivery present with a thick fibrinoid deposition at the utero-placental interface on microscopic examination independently of deeply implanted villous tissue in the sample. These changes are associated with distortion of the Nitabuch membrane and might explain the loss of parts of the physiological site of detachment of the placenta from the uterine wall in placenta accreta spectrum. These findings indicate that accreta placentation is more than direct attachment of the villous tissue to the superficial myometrium and support the concept that accreta villous tissue is not truly invasive.

Joan Hunt Senior award lecture: New tools to shed light on the 'black box' of pregnancy.

Correct establishment of the placenta is critical to the success of a pregnancy, but many of the key events take place during or shortly after implantation and are inaccessible for study. This inaccessibility, coupled with the lack of a suitable preclinical animal model, means that knowledge of human early placental development and function is extremely limited. Hence, the first trimester is often referred to as the 'black box' of pregnancy. However, recent advances in the derivation of trophoblast stem cells and organoid cultures of the trophoblast and endometrium are opening new opportunities for basic and translational research, providing for the first time cells that faithfully replicate their tissue of origin and proliferate and differentiate in culture in a stable and reproducible manner. These cells are valuable new tools for investigating cell-lineage differentiation and maternal-fetal interactions, but become even more powerful when combined with advances in bioengineering, microfabrication and microfluidic technologies. Assembloids of the endometrium comprising various cell types as model systems to investigate events at implantation, and placentas-on-a-chip for the study of nutrient transfer or drug screening are just two examples. This is a rapidly advancing field that may usher in more personalised approaches to infertility and pregnancy complications. Many of the developments are still at the proof-of-principle phase, but with continued refinement they are likely to shed important light on events that are fundamental to our reproduction as individuals and as a species, yet for ethical reasons are hidden from view.

The imprinted Igf2-Igf2r axis is critical for matching placental microvasculature expansion to fetal growth.

In all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but whether and how the latter adapts to putative fetal signals is currently unknown. Here, we demonstrate, through fetal, endothelial, hematopoietic, and trophoblast-specific genetic manipulations in the mouse, that endothelial and fetus-derived IGF2 is required for the continuous expansion of the feto-placental microvasculature in late pregnancy. The angiocrine effects of IGF2 on placental microvasculature expansion are mediated, in part, through IGF2R and angiopoietin-Tie2/TEK signaling. Additionally, IGF2 exerts IGF2R-ERK1/2-dependent pro-proliferative and angiogenic effects on primary feto-placental endothelial cells ex vivo. Endothelial and fetus-derived IGF2 also plays an important role in trophoblast morphogenesis, acting through Gcm1 and Synb. Thus, our study reveals a direct role for the imprinted Igf2-Igf2r axis on matching placental development to fetal growth and establishes the principle that hormone-like signals from the fetus play important roles in controlling placental microvasculature and trophoblast morphogenesis.