scholarly journals Human Cytomegalovirus Infection Interferes with the Maintenance and Differentiation of Trophoblast Progenitor Cells of the Human Placenta

2015 ◽  
Vol 89 (9) ◽  
pp. 5134-5147 ◽  
Author(s):  
Takako Tabata ◽  
Matthew Petitt ◽  
Martin Zydek ◽  
June Fang-Hoover ◽  
Nicholas Larocque ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Human Cytomegalovirus ◽  
Intrauterine Growth Restriction ◽  
Molecular Mechanisms ◽  
Hcmv Infection ◽  
Congenital Infection ◽  
Growth Restriction ◽  
Chorionic Villi ◽  
Intrauterine Growth

ABSTRACTHuman cytomegalovirus (HCMV) is a major cause of birth defects that include severe neurological deficits, hearing and vision loss, and intrauterine growth restriction. Viral infection of the placenta leads to development of avascular villi, edema, and hypoxia associated with symptomatic congenital infection. Studies of primary cytotrophoblasts (CTBs) revealed that HCMV infection impedes terminal stages of differentiation and invasion by various molecular mechanisms. We recently discovered that HCMV arrests earlier stages involving development of human trophoblast progenitor cells (TBPCs), which give rise to the mature cell types of chorionic villi—syncytiotrophoblasts on the surfaces of floating villi and invasive CTBs that remodel the uterine vasculature. Here, we show that viral proteins are present in TBPCs of the chorion in cases of symptomatic congenital infection.In vitrostudies revealed that HCMV replicates in continuously self-renewing TBPC lines derived from the chorion and alters expression and subcellular localization of proteins required for cell cycle progression, pluripotency, and early differentiation. In addition, treatment with a human monoclonal antibody to HCMV glycoprotein B rescues differentiation capacity, and thus, TBPCs have potential utility for evaluation of the efficacies of novel antiviral antibodies in protecting and restoring placental development. Our results suggest that HCMV replicates in TBPCs in the chorionin vivo, interfering with the earliest steps in the growth of new villi, contributing to virus transmission and impairing compensatory development. In cases of congenital infection, reduced responsiveness of the placenta to hypoxia limits the transport of substances from maternal blood and contributes to fetal growth restriction.IMPORTANCEHuman cytomegalovirus (HCMV) is a leading cause of birth defects in the United States. Congenital infection can result in permanent neurological defects, mental retardation, hearing loss, visual impairment, and pregnancy complications, including intrauterine growth restriction, preterm delivery, and stillbirth. Currently, there is neither a vaccine nor any approved treatment for congenital HCMV infection during gestation. The molecular mechanisms underlying structural deficiencies in the placenta that undermine fetal development are poorly understood. Here we report that HCMV replicates in trophoblast progenitor cells (TBPCs)—precursors of the mature placental cells, syncytiotrophoblasts and cytotrophoblasts, in chorionic villi—in clinical cases of congenital infection. Virus replication in TBPCsin vitrodysregulates key proteins required for self-renewal and differentiation and inhibits normal division and development into mature placental cells. Our findings provide insights into the underlying molecular mechanisms by which HCMV replication interferes with placental maturation and transport functions.

Intrauterine growth restriction-induced deleterious adaptations in endothelial progenitor cells: possible mechanism to impair endothelial function

2017 ◽  
Vol 8 (6) ◽  
pp. 665-673 ◽  
Author(s):  
V. Oliveira ◽  
L. V. de Souza ◽  
T. Fernandes ◽  
S. D. S. Junior ◽  
M. H. C. de Carvalho ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Functional Capacity ◽  
Intrauterine Growth Restriction ◽  
Vascular Reactivity ◽  
Growth Restriction ◽  
Intrauterine Growth ◽  
Ad Libitum

Intrauterine growth restriction (IUGR) can induce deleterious changes in the modulatory ability of the vascular endothelium, contributing to an increased risk of developing cardiovascular diseases in the long term. However, the mechanisms involved are not fully understood. Emerging evidence has suggested the potential role of endothelial progenitor cells (EPCs) in vascular health and repair. Therefore, we aimed to evaluate the effects of IUGR on vascular reactivity and EPCs derived from the peripheral blood (PB) and bone marrow (BM)in vitro. Pregnant Wistar rats were fed anad libitumdiet (control group) or 50% of thead libitumdiet (restricted group) throughout gestation. We determined vascular reactivity, nitric oxide (NO) concentration, and endothelial nitric oxide synthase (eNOS) protein expression by evaluating the thoracic aorta of adult male offspring from both groups (aged: 19–20 weeks). Moreover, the amount, functional capacity, and senescence of EPCs were assessedin vitro. Our results indicated that IUGR reduced vasodilation via acetylcholine in aorta rings, decreased NO levels, and increased eNOS phosphorylation at Thr495. The amount of EPCs was similar between both groups; however, IUGR decreased the functional capacity of EPCs from the PB and BM. Furthermore, the senescence process was accelerated in BM-derived EPCs from IUGR rats. In summary, our findings demonstrated the deleterious changes in EPCs from IUGR rats, such as reduced EPC function and accelerated senescencein vitro. These findings may contribute towards elucidating the possible mechanisms involved in endothelial dysfunction induced by fetal programming.

Melatonin-MT1 signal is essential for endometrial decidualization

Reproduction ◽  
2021 ◽  
Author(s):  
Liyuan Cui ◽  
Feng Xu ◽  
Songcun Wang ◽  
Zhuxuan Jiang ◽  
Lu Liu ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Intrauterine Growth Restriction ◽  
Growth Restriction ◽  
Endometrial Stromal Cells ◽  
Reproductive Process ◽  
Intrauterine Growth ◽  
In Vivo Experiments ◽  
Adverse Pregnancy

Deficient decidualization of endometrial stromal cells (ESCs) can cause adverse pregnancy outcomes including miscarriage, intrauterine growth restriction and pre-eclampsia. Decidualization is regulated by multiple factors such as hormones and circadian genes. Melatonin, a circadian-controlled hormone, is reported to be important for various reproductive process, including oocyte maturation and placenta development. Its receptor, MT1, is considered to be related to intrauterine growth restriction and pre-eclampsia. However, the role of melatonin-MT1 signal in decidualization remains unknown. Here, we reported that decidual stromal cells from miscarriages displayed deficient decidualization with decreased MT1 expression. The expression level of MT1 is gradually increased with the process of decidualization induction in vitro. MT1 knockdown suppressed decidualization level, while overexpression of MT1 promoted the decidualization process. Moreover, changing MT1 level could regulate the expression of decidualization-related transcription factor FOXO1. Melatonin promoted decidualization and reversed the decidualization deficiency due to MT1 knockdown. Using in vitro and in vivo experiments, we further identified that lipopolysaccharide (LPS) could induce inflammation and decidualization resistance with downregulated MT1 expression, and melatonin could reverse the inflammation and decidualization resistance induced by LPS. These results suggested melatonin-MT1 signal might be essential for decidualization and might provide a novel therapeutic target for decidualization deficiency-associated pregnancy complications.

scholarly journals Human Cytomegalovirus IE2 Protein Disturbs Brain Development by the Dysregulation of Neural Stem Cell Maintenance and the Polarization of Migrating Neurons

2017 ◽  
Vol 91 (17) ◽  
Author(s):  
Dasol Han ◽  
Sung-Hyun Byun ◽  
Juwan Kim ◽  
Mookwang Kwon ◽  
Samuel J. Pleasure ◽  
...  
Keyword(s):  
Stem Cell ◽  
Brain Development ◽  
Progenitor Cells ◽  
Neural Stem Cell ◽  
Human Cytomegalovirus ◽  
Neural Progenitor Cells ◽  
Hcmv Infection ◽  
Stem Cell Maintenance ◽  
Cell Maintenance

ABSTRACT Despite the high incidence of severe defects in the central nervous system caused by human cytomegalovirus (HCMV) congenital infection, the mechanism of HCMV neuropathogenesis and the roles of individual viral genes have not yet been fully determined. In this study, we show that the immediate-early 2 (IE2) protein may play a key role in HCMV-caused neurodevelopmental disorders. IE2-transduced neural progenitor cells gave rise to neurospheres with a lower frequency and produced smaller neurospheres than control cells in vitro, indicating reduction of self-renewal and expansion of neural progenitors by IE2. At 2 days after in utero electroporation into the ventricle of the developing brain, a dramatically lower percentage of IE2-expressing cells was detected in the ventricular zone (VZ) and cortical plate (CP) compared to control cells, suggesting that IE2 concurrently dysregulates neural stem cell maintenance in the VZ and neuronal migration to the CP. In addition, most IE2+ cells in the lower intermediate zone either showed multipolar morphology with short neurites or possessed nonradially oriented processes, whereas control cells had long, radially oriented monopolar or bipolar neurites. IE2+ callosal axons also failed to cross the midline to form the corpus callosum. Furthermore, we provide molecular evidence that the cell cycle arrest and DNA binding activities of IE2 appear to be responsible for the increased neural stem cell exit from the VZ and cortical migrational defects, respectively. Collectively, our results demonstrate that IE2 disrupts the orderly process of brain development in a stepwise manner to further our understanding of neurodevelopmental HCMV pathogenesis. IMPORTANCE HCMV brain pathogenesis has been studied in limited experimental settings, such as in vitro HCMV infection of neural progenitor cells or in vivo murine CMV infection of the mouse brain. Here, we show that IE2 is a pivotal factor that contributes to HCMV-induced abnormalities in the context of the embryonic brain using an in utero gene transfer tool. Surprisingly, IE2, but not HCMV IE1 or murine CMV ie3, interferes pleiotropically with key neurodevelopmental processes, including neural stem cell regulation, proper positioning of migrating neurons, and the callosal axon projections important for communication between the hemispheres. Our data suggest that the wide spectrum of clinical outcomes, ranging from mental retardation to microcephaly, caused by congenital HCMV infection can be sufficiently explained in terms of IE2 action alone.

Postnatal development of skeletal muscle in pigs with intrauterine growth restriction: morphofunctional phenotype and molecular mechanisms

2020 ◽  
Vol 236 (5) ◽  
pp. 840-853 ◽  
Author(s):  
Fernando Felicioni ◽  
Andreia D. Pereira ◽  
Andre L. Caldeira‐Brant ◽  
Thais G. Santos ◽  
Thais M. D. Paula ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Postnatal Development ◽  
Intrauterine Growth Restriction ◽  
Molecular Mechanisms ◽  
Growth Restriction ◽  
Intrauterine Growth

Intrauterine Growth Restriction Alters the Postnatal Development of the Rat Cerebellum

2017 ◽  
Vol 39 (1-4) ◽  
pp. 215-227 ◽  
Author(s):  
Annie R.A. McDougall ◽  
Vanny Wiradjaja ◽  
Aminath Azhan ◽  
Anqi Li ◽  
Nadia Hale ◽  
...  
Keyword(s):  
Intrauterine Growth Restriction ◽  
Molecular Mechanisms ◽  
Growth Restriction ◽  
Cerebellar Development ◽  
Mrna Levels ◽  
Fiber Density ◽  
Pregnant Rats ◽  
Intrauterine Growth ◽  
Protein Levels ◽  
Proliferative Zone

Intrauterine growth restriction (IUGR) is a major cause of antenatal brain injury. We aimed to characterize cerebellar deficits following IUGR and to investigate the potential underlying cellular and molecular mechanisms. At embryonic day 18, pregnant rats underwent either sham surgery (controls; n = 23) or bilateral uterine vessel ligation to restrict blood flow to fetuses (IUGR; n = 20). Offspring were collected at postnatal day 2 (P2), P7, and P35. Body weights were reduced at P2, P7, and P35 in IUGR offspring (p < 0.05) compared with controls. At P7, the width of the external granule layer (EGL) was 30% greater in IUGR than control rats (p < 0.05); there was no difference in the width of the proliferative zone or in the density of Ki67-positive cells in the EGL. Bergmann glia were disorganized at P7 and P35 in IUGR pups, and by P35, there was a 10% decrease in Bergmann glial fiber density (p < 0.05) compared with controls. At P7, trophoblast antigen-2 (Trop2) mRNA and protein levels in the cerebellum were decreased by 88 and 40%, respectively, and astrotactin 1 mRNA levels were increased by 20% in the IUGR rats (p < 0.05) compared with controls; there was no difference in ASTN1 protein. The expressions of other factors known to regulate cerebellar development (astrotactin 2, brain-derived neurotrophic factor, erb-b2 receptor tyrosine kinase 4, neuregulin 1, sonic hedgehog and somatostatin) were not different between IUGR and control rats at P7 or P35. These data suggest that damage to the migratory scaffold (Bergmann glial fibers) and alterations in the genes that influence migration (Trop2 and Astn1) may underlie the deficits in postnatal cerebellar development following IUGR.

Intrauterine Growth Restriction

2019 ◽  
pp. 11-16
Author(s):  
Robin D. Clark ◽  
Cynthia J. Curry
Keyword(s):  
Intrauterine Growth Restriction ◽  
Congenital Infection ◽  
Growth Restriction ◽  
Multiple Gestation ◽  
Intrauterine Growth ◽  
Panel Testing ◽  
Gene Panel Testing ◽  
Primordial Dwarfism ◽  
Or Gene ◽  
Silver Syndrome

This chapter reviews isolated and syndromic intrauterine growth restriction (IUGR) or small for gestational age infants. The differential diagnosis of intrauterine growth restriction includes placental, maternal, and fetal causes. Maternal causes of IUGR include exposure to teratogens, various maternal illnesses, and multiple gestation. Infant causes include congenital infection, chromosomal aneuploidy, and multiple syndromes including primordial dwarfism. Other causes include genomic imprinting errors (Russell Silver syndrome and IMAGe syndrome) and endocrine and metabolic causes, the lipodystrophies, and skeletal dysplasias including SHOX deficiency. The evaluation of IUGR usually includes a SNP microarray and often targeted or gene panel testing. A clinical case presentation features an infant with Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD II) .

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