Adenomyosis is a medical condition defined by the abnormal presence of endometrial tissue within the myometrium, in which fibrosis occurs with new collagen deposition and myofibroblast ...differentiation. In this study, the effect of several mediators and growth factors on collagen expression was investigated on human endometrial stromal cells (fibroblasts) derived from adenomyotic endometrium.
RT-PCR, Western blot analysis, pharmacological interventions and siRNA interference were applied to primary cultured human endometrial stromal cells (fibroblasts). Immunohistochemistry was used to analyze protein expression in adenomyotic endometrium tissue specimens.
Of the tested mediators, transforming growth factor β1 (TGFβ1) and its isoforms were effective to induce collagen and connective tissue growth factor (CTGF) expression. Collagen and CTGF induction by TGFβ1 could be reduced by the inhibitors targeting DNA transcription, protein translation, and Smad2/3 signaling. Interestingly, TGFβ1 induced Smad2/3 phosphorylation and CTGF mRNA expression, but not collagen mRNA expression, suggesting that TGFβ1 mediates collagen expression through CTGF induction and Smad2/3 activation. In parallel, TGFβ1 and CTGF also induced expression of heat shock protein (HSP) 47, a protein required for the synthesis of several types of collagens. However, only CTGF siRNA knockdown, could compromise TGFβ1-induced collagen expression. Finally, the immunohistochemistry revealed vimentin- and α-SMA-positive staining for (myo)fibroblasts, TGFβ1, collagen, and CTGF in the subepithelial stroma region of human adenomyotic endometria.
We reveal here that TGFβ1, collagen, and CTGF are expressed in the stroma of adenomyotic endometria and demonstrate that TGFβ1 can induce collagen production in endometrium-derived fibroblasts through cellular Smad2/3-dependent signaling pathway and CTGF expression, suggesting that endometrial TGFβ may take part in the pathogenesis of adenomyosis and ectopic endometrium may participate in uterine adenomyosis.
The combination of EGF, CHIR99021, A83-01, SB431542, VPA, and Y27632 (EGF/CASVY) facilitates the derivation of trophoblast stem (TS) cells from human blastocysts and first-trimester, but not term, ...cytotrophoblasts. The mechanism underlying this chemical induction of TS cells remains elusive. Here we demonstrate that the induction efficiency of cytotrophoblast is determined by functional antagonism of the placental transcription factor GCM1 and the stemness regulator ΔNp63α. ΔNp63α reduces GCM1 transcriptional activity, whereas GCM1 inhibits ΔNp63α oligomerization and autoregulation. EGF/CASVY cocktail activates ΔNp63α, thereby partially inhibiting GCM1 activity and reverting term cytotrophoblasts into stem cells. By applying hypoxia condition, we can further reduce GCM1 activity and successfully induce term cytotrophoblasts into TS cells. Consequently, we identify mitochondrial creatine kinase 1 (CKMT1) as a key GCM1 target crucial for syncytiotrophoblast differentiation and reveal decreased CKMT1 expression in preeclampsia. Our study delineates the molecular underpinnings of trophoblast stemness and differentiation and an efficient method to establish TS cells from term placentas.
Whether parental psychiatric disorders are associated with autism spectrum disorder (ASD) in offspring has remained inconclusive. We examined the associations of parental psychiatric disorders with ...ASD in offspring. This population‐based case–control study used Taiwan's National Health Insurance Research Database to identify a cohort of children born from 2004 to 2017 and their parents. A total of 24,279 children with ASD (diagnostic ICD‐9‐CM code: 299.x or ICD‐10 code F84.x) and 97,715 matched controls were included. Parental psychiatric disorders, including depressive disorders, bipolar spectrum disorders, anxiety disorders, obsessive–compulsive disorder, schizophrenia, substance use disorders, autism spectrum disorder, attention‐deficit hyperactivity disorder (ADHD), and adjustment disorders were identified. Conditional logistic regressions with covariate adjustment were performed. The results suggest that parental diagnosis with any of the psychiatric disorders is associated with ASD in offspring (adjusted odds ratio AOR = 1.45, 95%CI: 1.40–1.51 for mothers; and AOR = 1.12, 95%CI: 1.08–1.17 for fathers). ASD in offspring was associated with schizophrenia, depressive disorders, obsessive–compulsive disorder, adjustment disorders, ADHD and ASD in both parents. The relationship between parental psychiatric disorders and the timing of the child's birth and ASD diagnosis varied across the different psychiatric disorders. The present study provides supportive evidence that parental psychiatric disorders are associated with autistic children. Furthermore, because the associations between parental psychiatric disorders and the timing of child's birth and ASD diagnosis varied across psychiatric disorders, the observed relationships may be affected by both genetic and environmental factors. Future studies are needed to disentangle the potential influence of genetic and environmental factors on the observed associations.
Lay Summary
Parents of autistic children are more likely to have psychiatric disorders. This might partially be due to shared genetic factors between autism and other psychiatric disorders. In addition, rearing autistic children might be stressful, leading to increased possibility of psychiatric disorders among parents. We used Taiwan's National Health Insurance claims database to identify 24,279 autistic children and 4‐fold number of comparison children. The prevalence of psychiatric disorders among their parents were assessed. Specifically, we explored the temporal relationship between the timing of the diagnosis of parental psychiatric disorders and children's birth and autism diagnosis. We found parents of autistic children had higher risk of psychiatric disorders, especially for schizophrenia, depressive disorders, and adjustment disorders. Notably, we found that the risk of adjustment disorder was elevated after the child's birth. This finding indicates that the risk of parental psychiatric disorders may be attributable to not only genetic risk but also environmental factors, which are potentially modifiable. Further studies are needed to disentangle the influence of genetic and environmental factors and to determine effective intervention to reduce the risk of parental psychiatric disorders.
Animals are remarkably efficient in absorbing dietary fat and assimilating this energy-dense nutrient into the white adipose tissue (WAT) for storage. Although this metabolic efficiency may confer an ...advantage in times of calorie deprivation, it contributes to obesity and associated metabolic disorders when dietary fat is abundant. Here we show that the intestinal lipid synthesis enzyme acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has a crucial role in the assimilation of dietary fat and the accretion of body fat in mice. Mice lacking MGAT2 have a normal phenotype on a low-fat diet. However, on a high-fat diet, MGAT2-deficient mice are protected against developing obesity, glucose intolerance, hypercholesterolemia and fatty livers. Caloric intake is normal in MGAT2-deficient mice, and dietary fat is absorbed fully. However, entry of dietary fat into the circulation occurs at a reduced rate. This altered kinetics of fat absorption apparently results in more partitioning of dietary fat toward energy dissipation rather than toward storage in the WAT. Thus, our studies identify MGAT2 as a key determinant of energy metabolism in response to dietary fat and suggest that the inhibition of this enzyme may prove to be a useful strategy for treating obesity and other metabolic diseases associated with excessive fat intake.
ABSTRACT
Migration of placental extravillous trophoblast (EVT) cells into uterine decidua facilitates the establishment of blood circulation between mother and fetus and is modulated by EVT‐decidual ...cell interaction. Poor or excessive EVT migration is associated with pregnancy complications such as preeclampsia or placenta accreta. Glial cells missing 1 (GCM1) transcription factor is essential for placental development, and decreased GCM1 activity is detected in preeclampsia. To study whether GCM1 regulates trophoblast cell migration, here we showed that GCM1 promotes BeWo and JAR trophoblast cell migration through a novel target gene, WNT10B. Moreover, WNT10B signaling stimulated cytoskeletal remodeling via Rac1 and frizzled 7 (FZD7) was identified as the cognate receptor for WNT10B to up‐regulate cell migration. We further showed that secreted frizzled‐related protein 3 (SFRP3) is expressed in uterine decidual cells by immunohistochemistry and that SFRP3 expression in telomerase‐transformed human endometrial stromal cells (T‐HESCs) is elevated under decidualization stimuli and further enhanced by bone morphogenetic protein 2 via SMAD1. SFRP3 blocked the interaction between FZD7 and WNT10B to decrease BeWo cell migration, which corroborated the elevated BeWo cell migration when cocultured with decidualized and SFRP3‐knockdown T‐HESC monolayer. Our results suggest that GCM1 up‐regulates EVT cell migration through WNT10B and FZD7, which is negatively modulated by decidual SFRP3.—Wang, L.‐J., Lo, H.‐F., Lin, C.‐F., Ng, P.‐S., Wu, Y.‐H., Lee, Y.‐S., Cheong, M.‐L., Chen, H. SFRP3 negatively regulates placental extravillous trophoblast cell migration mediated by the GCM1‐WNT10B‐FZD7 axis. FASEB J. 33, 314–326 (2019). www.fasebj.org
To assess the relationship between gene expressions of the magnesium transporters and glucose parameters in pregnant women.
A cohort of women without ongoing or prior medical illnesses was recruited ...at the start of an early singleton pregnancy. Expression levels of the magnesium transporters—SLC41A1, CNNM2, MAGT1, TRPM6, and TRPM7—were assessed in the peripheral leukocytes, while total calcium and magnesium were assessed in the serum between 10 and 13 weeks gestation. Glucose parameters were assessed between 24 and 28 weeks gestation using the 75 g oral glucose tolerance test.
A total of 208 patients were included in the study. The expressions of the magnesium transports were generally unrelated to age, body mass index (BMI), or serum levels of calcium and magnesium. The magnesium transporters were correlated with each other at baseline (correlation coefficients: 0.31 to 0.51). BMI was a strong predictor of fasting glucose levels, while both BMI and age were strong predictors of post-load glucose levels. The expression of TRPM7 was found to be predictive of 1-h post-load blood glucose after accounting for the effects of age and BMI (β = −0.196, p = 0.020).
The increased maternal expression of the magnesium transporter TRPM7 may be associated with decreased glucose tolerance in pregnant women. In particular, the association between TRPM7 and 1-h post-load glucose levels was found to be independent of the effects of age and BMI. Future studies are needed to determine whether a mechanistic relationship can be demonstrated between TRPM7 and glucose metabolism.
Human trophoblast invasion of decidualized endometrium is essential for placentation and is tightly regulated and involves trophoblast-decidual cell interaction. High temperature requirement A4 ...(HtrA4) is a secreted serine protease highly expressed in the invasive extravillous trophoblasts that invade decidua. In contrast, both HtrA1 and HtrA3 have been shown to inhibit trophoblast invasion. Here we provide evidence that decidua-secreted HtrA1 and HtrA3 antagonize HtrA4-mediated trophoblast invasion. We demonstrated that HtrA1 and HtrA3 interact with and degrade HtrA4 and thereby inhibit trophoblast-like JAR cell invasion. Specifically, HtrA1 and HtrA3 expression is up-regulated under decidualization conditions in endometrial stromal and epithelial cells, T-HESCs and Ishikawa cells, respectively. Conditioned media from these two cell lines after decidualization treatment suppress HtrA4-expressing JAR cell invasion in an HtrA1- or HtrA3-dependent manner. Co-culture of the HtrA4-expressing JAR cells with decidualization stimuli-treated T-HESC or Ishikawa monolayer also impairs JAR cell invasion, which can be reversed by HtrA1 or HtrA3 knockdown, supporting that HtrA1 and HtrA3 are crucial for trophoblast-decidual cell interaction in the control of trophoblast invasion. Our study reveals a novel regulatory mechanism of trophoblast invasion through physical and functional interaction between HtrA family members.
PDF
