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Biology of Reproduction Jun 2022Fetal growth depends on placental function, which requires energy from mitochondria. Here we investigated whether mitochondrial function in the placenta relates to the...
Fetal growth depends on placental function, which requires energy from mitochondria. Here we investigated whether mitochondrial function in the placenta relates to the growth of the lightest and heaviest fetuses of each sex within the litter of mice. Placentas from the lightest and heaviest fetuses were taken to evaluate placenta morphology (stereology), mitochondrial energetics (high-resolution respirometry), mitochondrial regulators, nutrient transporters, hormone handling, and signaling pathways (qPCR and Western blotting). We found that mitochondrial complex I and II oxygen consumption rate was greater for placentas supporting the lightest female fetuses, although placental complex I abundance of the lightest females and complexes III and V of the lightest males were decreased compared to their heaviest counterparts. Expression of mitochondrial biogenesis (Nrf1) and fission (Drp1 and Fis1) genes was lower in the placenta from the lightest females, whilst biogenesis-related gene Tfam was greater in the placenta of the lightest male fetuses. In addition, placental morphology and steroidogenic gene (Cyp17a1 and Cyp11a1) expression were aberrant for the lightest females, but glucose transporter (Slc2a1) expression was lower in only the lightest males versus their heaviest counterparts. Differences in intra-litter placental phenotype were related to changes in the expression of hormone-responsive (androgen receptor) and metabolic signaling (AMPK, AKT, and PPARγ) pathways. Thus, in normal mouse pregnancy, placental structure, function, and mitochondrial phenotype are differentially responsive to the growth of the female and male fetus. This study may inform the design of sex-specific therapies for placental insufficiency and fetal growth abnormalities with life-long benefits for the offspring.
Topics: Animals; Female; Fetal Development; Hormones; Male; Mice; Mitochondria; Phenotype; Placenta; Pregnancy
PubMed: 35293971
DOI: 10.1093/biolre/ioac056 -
Proceedings of the National Academy of... Sep 2022Healthy progression of human pregnancy relies on cytotrophoblast (CTB) progenitor self-renewal and its differentiation toward multinucleated syncytiotrophoblasts (STBs)...
Healthy progression of human pregnancy relies on cytotrophoblast (CTB) progenitor self-renewal and its differentiation toward multinucleated syncytiotrophoblasts (STBs) and invasive extravillous trophoblasts (EVTs). However, the underlying molecular mechanisms that fine-tune CTB self-renewal or direct its differentiation toward STBs or EVTs during human placentation are poorly defined. Here, we show that Hippo signaling cofactor WW domain containing transcription regulator 1 (WWTR1) is a master regulator of trophoblast fate choice during human placentation. Using human trophoblast stem cells (human TSCs), primary CTBs, and human placental explants, we demonstrate that WWTR1 promotes self-renewal in human CTBs and is essential for their differentiation to EVTs. In contrast, WWTR1 prevents induction of the STB fate in undifferentiated CTBs. Our single-cell RNA sequencing analyses in first-trimester human placenta, along with mechanistic analyses in human TSCs revealed that WWTR1 fine-tunes trophoblast fate by directly regulating WNT signaling components. Importantly, our analyses of placentae from pathological pregnancies show that extreme preterm births (gestational time ≤28 wk) are often associated with loss of WWTR1 expression in CTBs. In summary, our findings establish the critical importance of WWTR1 at the crossroads of human trophoblast progenitor self-renewal versus differentiation. It plays positive instructive roles in promoting CTB self-renewal and EVT differentiation and safeguards undifferentiated CTBs from attaining the STB fate.
Topics: Cell Differentiation; Female; Hippo Signaling Pathway; Humans; Infant, Newborn; Placenta; Placentation; Pregnancy; Premature Birth; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Trophoblasts
PubMed: 36037374
DOI: 10.1073/pnas.2204069119 -
Scientific Reports Mar 2021Previously, we identified increased maternal circulating DAAM2 mRNA in pregnancies complicated by preterm fetal growth restriction (FGR). Here, we assessed whether... (Clinical Trial)
Clinical Trial
Previously, we identified increased maternal circulating DAAM2 mRNA in pregnancies complicated by preterm fetal growth restriction (FGR). Here, we assessed whether circulating DAAM2 mRNA could detect FGR, and whether the DAAM2 gene, known to play roles in the Wnt signalling pathway is expressed in human placenta and associated with dysfunction and FGR. We performed linear regression analysis to calculate area under the ROC curve (AUC) for DAAM2 mRNA expression in the maternal circulation of pregnancies complicated by preterm FGR. DAAM2 mRNA expression was assessed across gestation by qPCR. DAAM2 protein and mRNA expression was assessed in preterm FGR placenta using western blot and qPCR. DAAM2 expression was assessed in term cytotrophoblasts and placental explant tissue cultured under hypoxic and normoxic conditions by qPCR. Small interfering RNAs were used to silence DAAM2 in term primary cytotrophoblasts. Expression of growth, apoptosis and oxidative stress genes were assessed by qPCR. Circulating DAAM2 mRNA was elevated in pregnancies complicated by preterm FGR [p < 0.0001, AUC = 0.83 (0.78-0.89)]. Placental DAAM2 mRNA was detectable across gestation, with highest expression at term. DAAM2 protein was increased in preterm FGR placentas but demonstrated no change in mRNA expression. DAAM2 mRNA expression was increased in cytotrophoblasts and placental explants under hypoxia. Silencing DAAM2 under hypoxia decreased expression of pro-survival gene, BCL2 and oxidative stress marker, NOX4, whilst increasing expression of antioxidant enzyme, HMOX-1. The increased DAAM2 associated with FGR and hypoxia implicates a potential role in placental dysfunction. Decreasing DAAM2 may have cytoprotective effects, but further research is required to elucidate its role in healthy and dysfunctional placentas.
Topics: Adult; Female; Fetal Growth Retardation; Gene Expression Regulation; Humans; Hypoxia; Microfilament Proteins; Placenta; Pregnancy; RNA, Messenger; rho GTP-Binding Proteins
PubMed: 33692394
DOI: 10.1038/s41598-021-84785-7 -
International Journal of Molecular... Feb 2021Steroid hormones play a crucial role in supporting a successful pregnancy and ensuring proper fetal development. The placenta is one of the principal tissues in steroid...
Steroid hormones play a crucial role in supporting a successful pregnancy and ensuring proper fetal development. The placenta is one of the principal tissues in steroid production and metabolism, expressing a vast range of steroidogenic enzymes. Nevertheless, a comprehensive characterization of steroidogenic pathways in the human placenta and potential developmental changes occurring during gestation are poorly understood. Furthermore, the specific contribution of trophoblast cells in steroid release is largely unknown. Thus, this study aimed to (i) identify gestational age-dependent changes in the gene expression of key steroidogenic enzymes and (ii) explore the role of trophoblast cells in steroid biosynthesis and metabolism. Quantitative and Droplet Digital PCR analysis of 12 selected enzymes was carried out in the first trimester ( = 13) and term ( = 20) human placentas. Primary trophoblast cells ( = 5) isolated from human term placentas and choriocarcinoma-derived cell lines (BeWo, BeWo b30 clone, and JEG-3) were further screened for gene expression of enzymes involved in placental synthesis/metabolism of steroids. Finally, de novo steroid synthesis by primary human trophoblasts was evaluated, highlighting the functional activity of steroidogenic enzymes in these cells. Collectively, we provide insights into the expression patterns of steroidogenic enzymes as a function of gestational age and delineate the cellular origin of steroidogenesis in the human placenta.
Topics: Adult; Cells, Cultured; Choriocarcinoma; Female; Gene Expression Regulation; Gestational Age; Humans; Infant, Newborn; Placenta; Pregnancy; Pregnancy Trimester, First; Steroid Hydroxylases; Steroids; Trophoblasts
PubMed: 33567726
DOI: 10.3390/ijms22041704 -
Ultrasound in Obstetrics & Gynecology :... Jul 2023Evidence regarding placental function in pregnancies complicated by confined placental mosaicism (CPM) is conflicting. We aimed to compare placental function between CPM...
OBJECTIVES
Evidence regarding placental function in pregnancies complicated by confined placental mosaicism (CPM) is conflicting. We aimed to compare placental function between CPM and non-CPM pregnancies prenatally and at birth. A secondary objective was to evaluate the relationship between placental function and chromosomal subtype of CPM.
METHODS
This was a retrospective study of pregnancies with CPM and control pregnancies delivered at a tertiary hospital in Denmark between 2014 and 2017. Placental volume and placental transverse relaxation time (T2*) were estimated on magnetic resonance imaging (MRI), fetal weight and uterine artery pulsatility index (UtA-PI) were estimated on ultrasound and fetoplacental ratio was assessed on MRI and at birth. These estimates of placental function were adjusted for gestational age and compared between groups using the Wilcoxon rank-sum test. Within the group of CPM pregnancies, measures of placental function were compared between those at high risk (chromosome numbers 2, 3, 7, 13 and 16) and those at low risk (chromosome numbers 5, 18 and 45X).
RESULTS
A total of 90 pregnancies were included, of which 12 had CPM and 78 were controls. MRI and ultrasound examinations were performed at a median gestational age of 32.6 weeks (interquartile range, 24.7-35.3 weeks). On MRI assessment, CPM placentae were characterized by a lower placental T2* Z-score (P = 0.004), a lower fetoplacental ratio (P = 0.03) and a higher UtA-PI Z-score (P = 0.03), compared with non-CPM placentae. At birth, the fetoplacental ratio was significantly lower (P = 0.02) and placental weight Z-score was higher (P = 0.01) in CPM pregnancies compared with non-CPM pregnancies. High-risk CPM pregnancies showed a reduced placental T2* Z-score (P = 0.003), lower birth-weight Z-score (P = 0.041), earlier gestational age at delivery (P = 0.019) and higher UtA-PI Z-score (P = 0.028) compared with low-risk CPM pregnancies. Low-risk CPM pregnancies did not differ in any of these parameters from non-CPM pregnancies.
CONCLUSIONS
CPM pregnancies are characterized by an enlarged and dysfunctional placenta. Placental function was highly related to the chromosomal type of CPM; placental dysfunction was seen predominantly in high-risk CPM pregnancies in which chromosomes 2, 3, 7, 13 or 16 were involved. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Infant; Placenta; Infant, Small for Gestational Age; Mosaicism; Retrospective Studies; Ultrasonography, Prenatal; Gestational Age; Parturition; Magnetic Resonance Imaging; Uterine Artery
PubMed: 36730148
DOI: 10.1002/uog.26174 -
Journal of Animal Science Apr 2020Mammals have a circadian rhythm that is synchronized by a master clock located in the hypothalamic suprachiasmatic nucleus (SCN). The SCN regulates additional clocks...
Mammals have a circadian rhythm that is synchronized by a master clock located in the hypothalamic suprachiasmatic nucleus (SCN). The SCN regulates additional clocks located in peripheral tissues, including some involved in endocrine or reproductive functions. Studies in humans and mice report that molecular clocks also exist in the placenta. However, little is known about the presence of "Clock genes," namely Circadian Locomotor Output Cycles Kaput (CLOCK), Brain and Muscle Arnt-Like 1 (BMAL1), Period 1 (PER1), Period 2 (PER2), Cryptochrome 1 (CRY1), and Cryptochrome 2 (CRY2), in equine placenta. Pregnancy length in mares varies and shows fluctuations in hormone concentrations throughout pregnancy. We postulate that similar to humans and mice, Clock genes are present in the horse placentas. Our goal was to determine if relative levels of clock genes were different between placentas associated with males and female fetuses or correlated with gestational length. We used polymerase chain reaction and immunofluorescence to study the presence of CLOCK, BMAL1, PER1, PER2, CRY1, and CRY2 in full-term mare placentas. Clock genes were present in all placentas, with significant lower levels of CRY2 and CLOCK in placentas that were associated with male fetuses. There was no association between relative levels of Clock genes and gestational length. These data provide the stage for future studies aimed at uncovering a function for Clock genes in the horse placenta.
Topics: Animals; CLOCK Proteins; Female; Gene Expression Regulation; Horses; Male; Placenta; Pregnancy
PubMed: 32211788
DOI: 10.1093/jas/skaa094 -
International Journal of Molecular... Dec 2022As the mediator between the mother and fetus, the placenta allows the most appropriate environment and optimal fetal growth. The placenta of one sex sometimes has a...
As the mediator between the mother and fetus, the placenta allows the most appropriate environment and optimal fetal growth. The placenta of one sex sometimes has a greater ability over the other to respond to and protect against possible maternal insults. Here, we characterized sex differences in the placenta’s morphological features and antioxidant status following dexamethasone (Dx) exposure. Pregnant rats were exposed to Dx or saline. The placenta was histologically and stereologically analyzed. The activity of the antioxidant enzymes, lipid peroxides (TBARS), superoxide anion and nitric oxide (NO) was measured. The decrease in placental zone volumes was more pronounced (p < 0.05) in female placentas. The volume density of PCNA-immunopositive nuclei was reduced (p < 0.05) in both sexes. The reduced (p < 0.05) antioxidant enzyme activities, enhanced TBARS and NO concentration indicate that Dx exposure triggered oxidative stress in the placenta of both fetal sexes, albeit stronger in the placenta of female fetuses. In conclusion, maternal Dx treatment reduced the size and volume of placental zones, altered placental histomorphology, decreased cell proliferation and triggered oxidative stress; however, the placentas of female fetuses exerted more significant responses to the treatment effects. The reduced placental size most probably reduced the transport of nutrients and oxygen, thus resulting in the reduced weight of fetuses, similar in both sexes. The lesser ability of the male placenta to detect and react to maternal exposure to environmental challenges may lead to long-standing health effects.
Topics: Animals; Female; Male; Pregnancy; Rats; Antioxidants; Dexamethasone; Maternal Exposure; Oxidation-Reduction; Placenta; Thiobarbituric Acid Reactive Substances
PubMed: 36613982
DOI: 10.3390/ijms24010540 -
American Journal of Obstetrics and... Mar 2021Although there is some evidence that severe acute respiratory syndrome coronavirus 2 can invade the human placenta, limited data exist on the gestational age-dependent...
Expression of severe acute respiratory syndrome coronavirus 2 cell entry genes, angiotensin-converting enzyme 2 and transmembrane protease serine 2, in the placenta across gestation and at the maternal-fetal interface in pregnancies complicated by preterm birth or preeclampsia.
BACKGROUND
Although there is some evidence that severe acute respiratory syndrome coronavirus 2 can invade the human placenta, limited data exist on the gestational age-dependent expression profile of the severe acute respiratory syndrome coronavirus 2 cell entry mediators, angiotensin-converting enzyme 2 and transmembrane protease serine 2, at the human maternal-fetal interface. There is also no information as to whether the expression of these mediators is altered in pregnancies complicated by preeclampsia or preterm birth. This is important because the expression of decidual and placental angiotensin-converting enzyme 2 and transmembrane protease serine 2 across gestation may affect the susceptibility of pregnancies to vertical transmission of severe acute respiratory syndrome coronavirus 2.
OBJECTIVE
This study aimed to investigate the expression pattern of specific severe acute respiratory syndrome coronavirus 2 cell entry genes, angiotensin-converting enzyme 2 and transmembrane protease serine 2, in the placenta across human pregnancy and in paired samples of decidua and placenta in pregnancies complicated by preterm birth or preeclampsia compared with those in term uncomplicated pregnancies.
STUDY DESIGN
In this study, 2 separate cohorts of patients, totaling 87 pregnancies, were included. The first cohort was composed of placentae from first- (7-9 weeks), second- (16-18 weeks), and third-trimester preterm (26-31 weeks) and third-trimester term (38-41 weeks) pregnancies (n=5/group), whereas the second independent cohort included matched decidua and placentae from pregnancies from term uncomplicated pregnancies (37-41 weeks' gestation; n=14) and pregnancies complicated by preterm birth (26-37 weeks' gestation; n=11) or preeclampsia (25-37 weeks' gestation; n=42). Samples were subjected to quantitative polymerase chain reaction and next-generation sequencing or RNA sequencing for next-generation RNA sequencing for angiotensin-converting enzyme 2 and transmembrane protease serine 2 mRNA expression quantification, respectively.
RESULTS
In the first cohort, angiotensin-converting enzyme 2 and transmembrane protease serine 2, exhibited a gestational age-dependent expression profile, that is, angiotensin-converting enzyme 2 and transmembrane protease serine 2 mRNA was higher (P<.05) in the first-trimester placenta than in second-trimester, preterm birth, and term placentae (P<.05) and exhibited a negative correlation with gestational age (P<.05). In the second cohort, RNA sequencing demonstrated very low or undetectable expression levels of angiotensin-converting enzyme 2 in preterm birth, preeclampsia, and term decidua and in placentae from late gestation. In contrast, transmembrane protease serine 2 was expressed in both decidual and placental samples but did not change in pregnancies complicated by either preterm birth or preeclampsia.
CONCLUSION
The increased expression of these severe acute respiratory syndrome coronavirus 2 cell entry-associated genes in the placenta in the first trimester of pregnancy compared with those in later stages of pregnancy suggests the possibility of differential susceptibility to placental entry to severe acute respiratory syndrome coronavirus 2 across pregnancy. Even though there is some evidence of increased rates of preterm birth associated with severe acute respiratory syndrome coronavirus 2 infection, we found no increase in mRNA expression of angiotensin-converting enzyme 2 or transmembrane protease serine 2 at the maternal-fetal interface.
Topics: Angiotensin-Converting Enzyme 2; COVID-19; Female; Humans; Placenta; Pre-Eclampsia; Pregnancy; Premature Birth; RNA, Messenger; SARS-CoV-2; Serine Endopeptidases; Virus Internalization
PubMed: 32853537
DOI: 10.1016/j.ajog.2020.08.055 -
Experimental Biology and Medicine... Oct 2023Gestational diabetes mellitus (GDM) is a common complication during pregnancy, which can have harmful health consequences for both the mother and the fetus. Given the...
Gestational diabetes mellitus (GDM) is a common complication during pregnancy, which can have harmful health consequences for both the mother and the fetus. Given the placenta's crucial role as an endocrine organ during pregnancy, exploring and validating key genes in the placenta hold significant potential in the realm of GDM prevention and treatment. In this study, differentially expressed genes (DEGs) were identified from two databases, GSE70493 and PRJNA646212, and verified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in placenta tissues. DEGs expression was detected in normal or high-glucose-treated HTR8/SVneo cells. We also investigated the relationship between DEGs and glucose levels in GDM patients. By selecting the intersection of the two databases, we screened 20 DEGs, which were validated in GDM patients. We observed an up-regulation of SLAMF, ALDH1A2, and CHI3L2, and a down-regulation of HLA-E, MYH11, HLA-DRB5, ITGAX, GZMB, NAIP, TMEM74B, RANBP3L, PAEP, WT-1, and CEP170. We conducted further investigations into the expression of DEGs in HTR8/SVneo cells exposed to high glucose, revealing a significant upregulation in the expression of SERPINA3, while the expressions of HLA-E, BCL6, NAIP, PAEP, MUC16, WT-1, and CEP170 were decreased. Moreover, some DEGs were confirmed to have a positive or negative correlation with blood glucose levels of GDM patients through correlation analysis. The identified DEGs are anticipated to exert potential implications in the prevention and management of GDM, thereby offering potential benefits for improving pregnancy outcomes and long-term prognosis of fetuses among individuals affected by GDM.
Topics: Pregnancy; Female; Humans; Diabetes, Gestational; HLA-E Antigens; Placenta; Down-Regulation; Glucose; Chitinases
PubMed: 37873933
DOI: 10.1177/15353702231199077 -
Molecular Biology and Evolution Oct 2021In mammals, the placenta mediates maternal-fetal nutrient and waste exchange and acts in an immunomodulatory way to facilitate maternal-fetal tolerance. The placenta is...
In mammals, the placenta mediates maternal-fetal nutrient and waste exchange and acts in an immunomodulatory way to facilitate maternal-fetal tolerance. The placenta is highly diverse across mammalian species, yet the molecular mechanisms that distinguish the placenta of human from other mammals are not fully understood. Using an interspecies transcriptomic comparison of human, macaque, and mouse late-gestation placentae, we identified hundreds of genes with lineage-specific expression-including dozens that are placentally enriched and potentially related to pregnancy. We further annotated the enhancers for different human tissues using epigenomic data and demonstrate that the placenta and chorion are unique in that their enhancers display the least conservation. We identified numerous lineage-specific human placental enhancers and found they highly overlap with specific families of endogenous retroviruses (ERVs), including MER21A, MER41A/B, and MER39B that were previously linked to immune response and placental function. Among these ERV families, we further demonstrate that MER41A/B insertions create dozens of lineage-specific serum response factor-binding loci in human, including one adjacent to FBN2, a placenta-specific gene with increased expression in humans that produces the peptide hormone placensin to stimulate glucose secretion and trophoblast invasion. Overall, our results demonstrate the prevalence of lineage-specific placental enhancers which are frequently associated with ERV insertions and likely facilitate the lineage-specific evolution of the mammalian placenta.
Topics: Animals; Endogenous Retroviruses; Female; Mice; Placenta; Pregnancy; Primates; Rodentia; Trophoblasts
PubMed: 34320657
DOI: 10.1093/molbev/msab223