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1.
Placenta ; 101: 57-65, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32927345

RESUMO

BACKGROUND: Birthweight is a critical predictor of congenital heart disease (CHD) surgical outcomes. Hypoplastic left heart syndrome (HLHS) is cyanotic CHD with known fetal growth restriction and placental abnormalities. Transposition of the great arteries (TGA) is cyanotic CHD with normal fetal growth. Comparison of the placenta in these diagnoses may provide insights on the fetal growth abnormality of CHD. METHODS: Clinical data and placental histology from placentas associated with Transposition of the Great Arteries (TGA) were analyzed for gross pathology, morphology, maturity and vascularity and compared to both control and previously analyzed HLHS placentas [1]. RNA was isolated from HLHS, TGA and control placentas and sequenced by Illumina HiSeq.Transcriptome analysis was performed using AltAnalyze. Immunohistochemistry was utilized to assess placental nutrient transporter expression in all three groups. RESULTS: Placental weight was reduced in TGA cases, and demonstrated reduced villous vasculature, immature terminal villi in the parenchyma compared to controls and reflected our previous data from HLHS placentas. However, birth weight was not reduced in TGA cases compared to controls in contrast to the HLHS cohort and birthweight:placental weight ratio was significantly increased in TGA cases but not HLHS compared to control. Transcriptomic and histologic analysis demonstrates reduced cell activity and nutrient transport capability in HLHS but not TGA placentas which appear to increase/maintain these mechanisms. CONCLUSIONS: Despite common vascular disturbances in placentas from HLHAs and TGA, these do not account for the disparities in birthweights frequently seen between these CHD subtypes, in contrast our transcriptomic and histologic analyses reveal differentially regulated mechanisms between the subtypes that may explain these disparities.


Assuntos
Doenças Fetais/patologia , Síndrome do Coração Esquerdo Hipoplásico/patologia , Proteínas de Membrana Transportadoras/metabolismo , Placenta/patologia , Transposição dos Grandes Vasos/patologia , Adulto , Feminino , Doenças Fetais/metabolismo , Humanos , Síndrome do Coração Esquerdo Hipoplásico/metabolismo , Placenta/metabolismo , Gravidez , Estudos Retrospectivos , Transcriptoma , Transposição dos Grandes Vasos/metabolismo , Adulto Jovem
2.
Placenta ; 93: 1-7, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32090963

RESUMO

INTRODUCTION: Placental dysfunction is an underlying cause of many major obstetric diseases and treatment options for complications like fetal growth restriction (FGR) are limited .We previously demonstrated nanoparticle delivery of the human insulin-like growth factor 1 (hIGF1) transgene under control of the trophoblast-specific PLAC1 promoter maintains normal fetal growth in a surgically-induced FGR mouse model. However, uptake by human placental syncytiotrophoblast has yet to be determined. METHODS: An ex vivo human placenta perfusion model, term placenta villous fragments, and other in vitro syncytiotrophoblast models were used to determine nanoparticle uptake, transgene expression, and functional responses under oxidative stress conditions. RESULTS: In the ex vivo perfusion, fluorescence from a Texas-Red conjugated nanoparticle increased in maternal perfusate upon nanoparticle addition and declined by the conclusion of the experiment (P < 0.001. Fluorescent histology confirmed localization in the syncytiotrophoblasts. No Texas-Red fluorescence was detected in the fetal perfusate. Transgene expression of hIGF1 in differentiated BeWo cells, isolated primary trophoblasts and fragments was increased compared to untreated (55,000-fold, P = 0.0003; 95-fold, P = 0.003; 400-fold, P < 0.001, respectively). Functionally, increased hIGF1 expression in villous fragments resulted in translocation of glucose transporter 1 to the syncytiotrophoblast cell membrane and under conditions of oxidative stress in BeWo cells, protected against increased cell death (P < 0.01) and decreased mitochondrial activity (P < 0.01). CONCLUSION: The current study confirms that our nanoparticle is capable of uptake in human placental syncytium which results in enhanced transgene expression, functional changes to cellular activity and protection against increased oxidative stress.


Assuntos
Técnicas de Transferência de Genes , Células Gigantes/metabolismo , Fator de Crescimento Insulin-Like I/genética , Nanopartículas , Placenta/metabolismo , Trofoblastos/metabolismo , Adulto , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Células Cultivadas , Portadores de Fármacos/farmacologia , Feminino , Expressão Gênica/efeitos dos fármacos , Células Gigantes/efeitos dos fármacos , Humanos , Recém-Nascido , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Nanopartículas/química , Placenta/citologia , Placenta/efeitos dos fármacos , Gravidez , Transfecção/métodos , Trofoblastos/efeitos dos fármacos , Trofoblastos/fisiologia
3.
Sci Rep ; 8(1): 10638, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30006626

RESUMO

Spina bifida aperta is a congenital malformation characterized by the failure of neural tube closure resulting in an unprotected fetal spinal cord. The spinal cord then undergoes progressive damage, likely due to chemical and mechanical factors related to exposure to the intrauterine environment. Astrogliosis in exposed spinal cords has been described in animal models of spina bifida during embryonic life but its relationship with neuroinflammatory processes are completely unknown. Using a retinoic acid-induced rat model of spina bifida we demonstrated that, when exposed to amniotic fluid, fetal spinal cords showed progressive astrogliosis with neuronal loss at mid-gestation (E15) compared to unexposed spinal cords. The number of microglial cells with a reactive phenotype and activation marker expression increased during gestation and exhibited progressive disruption in the inhibitory immune ligand-receptor system. Specifically we demonstrate down-regulation of CD200 expression and up-regulation of CD200R. Exposed spinal cords demonstrated neuroinflammation with increased tissue water content and cytokine production by the end of gestation (E20), which correlated with active Caspase3 expression in the exposed layers. Our findings provide new evidence that microglia activation, including the disruption of the endogenous inhibitory system (CD200-CD200R), may participate in the pathogenesis of spina bifida through late gestation.


Assuntos
Líquido Amniótico/imunologia , Antígenos CD/metabolismo , Microglia/metabolismo , Receptores Imunológicos/metabolismo , Espinha Bífida Cística/imunologia , Líquido Amniótico/metabolismo , Animais , Antígenos CD/imunologia , Caspase 3/imunologia , Caspase 3/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Embrião de Mamíferos , Feminino , Humanos , Microglia/imunologia , Gravidez , Ratos , Ratos Sprague-Dawley , Receptores Imunológicos/imunologia , Espinha Bífida Cística/induzido quimicamente , Espinha Bífida Cística/patologia , Medula Espinal/citologia , Medula Espinal/imunologia , Medula Espinal/patologia , Tretinoína/toxicidade , Regulação para Cima
4.
Genome Res ; 27(3): 349-361, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28174237

RESUMO

Organismal function is, to a great extent, determined by interactions among their fundamental building blocks, the cells. In this work, we studied the cell-cell interactome of fetal placental trophoblast cells and maternal endometrial stromal cells, using single-cell transcriptomics. The placental interface mediates the interaction between two semiallogenic individuals, the mother and the fetus, and is thus the epitome of cell interactions. To study these, we inferred the cell-cell interactome by assessing the gene expression of receptor-ligand pairs across cell types. We find a highly cell-type-specific expression of G-protein-coupled receptors, implying that ligand-receptor profiles could be a reliable tool for cell type identification. Furthermore, we find that uterine decidual cells represent a cell-cell interaction hub with a large number of potential incoming and outgoing signals. Decidual cells differentiate from their precursors, the endometrial stromal fibroblasts, during uterine preparation for pregnancy. We show that decidualization (even in vitro) enhances the ability to communicate with the fetus, as most of the receptors and ligands up-regulated during decidualization have their counterpart expressed in trophoblast cells. Among the signals transmitted, growth factors and immune signals dominate, and suggest a delicate balance of enhancing and suppressive signals. Finally, this study provides a rich resource of gene expression profiles of term intravillous and extravillous trophoblasts, including the transcriptome of the multinucleated syncytiotrophoblast.


Assuntos
Comunicação Celular , Decídua/metabolismo , Troca Materno-Fetal , Transcriptoma , Linhagem Celular , Células Cultivadas , Decídua/citologia , Feminino , Humanos , Gravidez , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Análise de Célula Única , Regulação para Cima
5.
Int J Radiat Biol ; 92(11): 665-678, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26967573

RESUMO

To establish metabolic context for radiation sensitivity by measuring autophagic flux in two different glioblastoma (GBM) cell lines. Clonogenic survival curve analysis of U87 or U251 cells exposed to γ radiation, fast neutrons, a mixed energy neutron beam (METNB) or Auger electrons from a gadolinium neutron capture (GdNC) reaction suggested other factors, beyond a defective DNA damage response, contribute to cell death of U251 cells. Altered tumor metabolism (autophagy) was hypothesized as a factor in U251 cells' clonogenic response. Each of the four different radiation modalities induced an increase in the number of autophagosomes in both U87 and U251 cells. Changes in the number of autophagosomes can be explained by either induction of autophagy or alterations in autophagic flux so autophagic flux was assayed by p62 immunoblotting or in engineered GBM cells that stably express an autophagy marker protein, LC3B-eGFP-mCherry. Perturbations in later stages of autophagy in U251 cells corresponded with radiation sensitivity of U251 cells irradiated with 10 Gy γ rays. Establishment of altered autophagic flux is a useful biomarker for metabolic stress and provided metabolic context for radiation sensitization to 10 Gy γ rays. These results provide strong evidence for the usefulness of managing tumor cell metabolism as a tool for the enhancement of radiation therapy.


Assuntos
Autofagossomos/efeitos da radiação , Autofagia/efeitos da radiação , Dano ao DNA , Elétrons/uso terapêutico , Glioblastoma/genética , Glioblastoma/radioterapia , Autofagossomos/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta à Radiação , Raios gama/uso terapêutico , Glioblastoma/patologia , Humanos , Nêutrons/uso terapêutico , Dosagem Radioterapêutica
6.
PLoS One ; 10(10): e0140879, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26473479

RESUMO

Low birth weight is associated with both short term problems and the fetal programming of adult onset diseases, including an increased risk of obesity, diabetes and cardiovascular disease. Placental insufficiency leading to intrauterine growth restriction (IUGR) contributes to the prevalence of diseases with developmental origins. Currently there are no therapies for IUGR or placental insufficiency. To address this and move towards development of an in utero therapy, we employ a nanostructure delivery system complexed with the IGF-1 gene to treat the placenta. IGF-1 is a growth factor critical to achieving appropriate placental and fetal growth. Delivery of genes to a model of human trophoblast and mouse placenta was achieved using a diblock copolymer (pHPMA-b-pDMAEMA) complexed to hIGF-1 plasmid DNA under the control of trophoblast-specific promoters (Cyp19a or PLAC1). Transfection efficiency of pEGFP-C1-containing nanocarriers in BeWo cells and non-trophoblast cells was visually assessed via fluorescence microscopy. In vivo transfection and functionality was assessed by direct placental-injection into a mouse model of IUGR. Complexes formed using pHPMA-b-pDMAEMA and CYP19a-923 or PLAC1-modified plasmids induce trophoblast-selective transgene expression in vitro, and placental injection of PLAC1-hIGF-1 produces measurable RNA expression and alleviates IUGR in our mouse model, consequently representing innovative building blocks towards human placental gene therapies.


Assuntos
Técnicas de Transferência de Genes , Terapia Genética/métodos , Fator de Crescimento Insulin-Like I/biossíntese , Insuficiência Placentária/terapia , Trofoblastos/metabolismo , Animais , Aromatase/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Fator de Crescimento Insulin-Like I/genética , Camundongos , Insuficiência Placentária/genética , Insuficiência Placentária/metabolismo , Insuficiência Placentária/patologia , Gravidez , Proteínas da Gravidez/genética , Regiões Promotoras Genéticas , Trofoblastos/patologia
7.
Placenta ; 36(10): 1078-86, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26278057

RESUMO

INTRODUCTION: Hypoplastic left heart syndrome (HLHS) is a severe cardiovascular malformation (CVM) associated with fetal growth abnormalities. Genetic and environmental factors have been identified that contribute to pathogenesis, but the role of the placenta is unknown. The purpose of this study was to systematically examine the placenta in HLHS with and without growth abnormalities. METHODS: HLHS term singleton births were identified from a larger cohort when placenta tissue was available. Clinical data were collected from maternal and neonatal medical records, including anthropometrics and placental pathology reports. Placental tissues from cases and controls were analyzed to assess parenchymal morphology, vascular architecture and leptin signaling. RESULTS: HLHS cases (n = 16) and gestational age-matched controls (n = 18) were analyzed. Among cases, the average birth weight was 2993 g, including 31% that were small for gestational age. When compared with controls, gross pathology of HLHS cases demonstrated significantly reduced placental weight and increased fibrin deposition, while micropathology showed increased syncytial nuclear aggregates, decreased terminal villi, reduced vasculature and increased leptin expression in syncytiotrophoblast and endothelial cells. DISCUSSION: Placentas from pregnancies complicated by fetal HLHS are characterized by abnormal parenchymal morphology, suggesting immature structure may be due to vascular abnormalities. Increased leptin expression may indicate an attempt to compensate for these vascular abnormalities. Further investigation into the regulation of angiogenesis in the fetus and placenta may elucidate the causes of HLHS and associated growth abnormalities in some cases.


Assuntos
Peso ao Nascer , Síndrome do Coração Esquerdo Hipoplásico/patologia , Leptina/metabolismo , Placenta/patologia , Feminino , Fibrina/metabolismo , Humanos , Síndrome do Coração Esquerdo Hipoplásico/metabolismo , Tamanho do Órgão , Placenta/irrigação sanguínea , Placenta/metabolismo , Fator de Crescimento Placentário , Gravidez , Proteínas da Gravidez/metabolismo , Receptores para Leptina/metabolismo , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
8.
J Clin Invest ; 125(4): 1713-25, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25751061

RESUMO

Mammalian pregnancy requires protection against immunological rejection of the developing fetus bearing discordant paternal antigens. Immune evasion in this developmental context entails silenced expression of chemoattractant proteins (chemokines), thereby preventing harmful immune cells from penetrating the maternal-fetal interface. Here, we demonstrate that fetal wastage triggered by prenatal Listeria monocytogenes infection is driven by placental recruitment of CXCL9-producing inflammatory neutrophils and macrophages that promote infiltration of fetal-specific T cells into the decidua. Maternal CD8+ T cells with fetal specificity upregulated expression of the chemokine receptor CXCR3 and, together with neutrophils and macrophages, were essential for L. monocytogenes-induced fetal resorption. Conversely, decidual accumulation of maternal T cells with fetal specificity and fetal wastage were extinguished by CXCR3 blockade or in CXCR3-deficient mice. Remarkably, protection against fetal wastage and in utero L. monocytogenes invasion was maintained even when CXCR3 neutralization was initiated after infection, and this protective effect extended to fetal resorption triggered by partial ablation of immune-suppressive maternal Tregs, which expand during pregnancy to sustain fetal tolerance. Together, our results indicate that functionally overriding chemokine silencing at the maternal-fetal interface promotes the pathogenesis of prenatal infection and suggest that therapeutically reinforcing this pathway represents a universal approach for mitigating immune-mediated pregnancy complications.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Morte Fetal/prevenção & controle , Listeriose/imunologia , Complicações Infecciosas na Gravidez/imunologia , Receptores CXCR3/fisiologia , Subpopulações de Linfócitos T/imunologia , Transferência Adotiva , Ampicilina/uso terapêutico , Animais , Antibacterianos/uso terapêutico , Quimiocina CXCL9/biossíntese , Quimiocina CXCL9/genética , Quimiocina CXCL9/fisiologia , Quimiocinas/metabolismo , Cruzamentos Genéticos , Decídua/imunologia , Feminino , Morte Fetal/etiologia , Reabsorção do Feto/imunologia , Reabsorção do Feto/prevenção & controle , Listeriose/tratamento farmacológico , Macrófagos/imunologia , Masculino , Troca Materno-Fetal , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neutrófilos/imunologia , Ovalbumina/genética , Ovalbumina/imunologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/imunologia , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Receptores CXCR3/antagonistas & inibidores , Receptores CXCR3/biossíntese , Receptores CXCR3/deficiência , Receptores CXCR3/genética , Baço/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T Reguladores/imunologia , Regulação para Cima , Virulência
10.
Int J Radiat Biol ; 88(12): 980-90, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22849307

RESUMO

PURPOSE: A comparative study of the effects of different radiation modalities on cell death was performed. MATERIALS AND METHODS: Radiation modalities included γ-rays, fast neutrons, a mixed energy neutron beam called the modified enhanced thermal neutron beam and the mixed beam including Auger electron irradiation by gadolinium neutron capture. U87 (human brain tumor cells) cell survival curve data were modeled to predict how cells died. Transmission electron microscopy (TEM) images were assembled into a morphology of cell death (MCD) database and used to determine the fraction of necrotic or autophagic cells. RESULTS: Linear energy transfer (LET) differences for the different radiation modalities were revealed by modeling. All radiation modalities induced autophagy but only fast neutrons induced significant levels of necrosis. No necrosis, above control levels, was found in cells irradiated with mixed beam irradiation including Auger electrons. The number of autophagosomes increased with increasing time after exposure to all radiation modalities indicating progression of autophagy but only cells irradiated with the mixed beam plus Auger electrons exhibited extreme autophagy. CONCLUSIONS: Mixed neutron beam irradiation plus Auger electron irradiation from gadolinium neutron capture is a moderately high LET modality that kills U87 cells without the induction of necrosis and with progression of autophagy to an extreme state.


Assuntos
Gadolínio/uso terapêutico , Glioblastoma/patologia , Terapia por Captura de Nêutron/métodos , Autofagia/efeitos da radiação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Glioblastoma/radioterapia , Humanos , Necrose/etiologia
11.
Science ; 296(5566): 331-3, 2002 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-11884719

RESUMO

The strontium-to-calcium ratio (Sr/Ca) of reef coral skeleton is commonly used as a paleothermometer to estimate sea surface temperatures (SSTs) at crucial times in Earth's climate history. However, these estimates are disputed, because uptake of Sr into coral skeleton is thought to be affected by algal symbionts (zooxanthellae) living in the host tissue. Here, we show that significant distortion of the Sr/Ca temperature record in coral skeleton occurs in the presence of algal symbionts. Seasonally resolved Sr/Ca in coral without symbionts reflects local SSTs with a temperature sensitivity equivalent to that of laboratory aragonite precipitated at equilibrium and the nighttime skeletal deposits of symbiotic reef corals. However, up to 65% of the Sr/Ca variability in symbiotic skeleton is related to symbiont activity and does not reflect water temperature.


Assuntos
Carbonato de Cálcio/química , Clima , Cnidários/química , Eucariotos/fisiologia , Água do Mar , Simbiose , Animais , Oceano Atlântico , Cálcio/análise , Cnidários/crescimento & desenvolvimento , Cnidários/fisiologia , Fotossíntese , Estações do Ano , Estrôncio/análise , Temperatura , Tempo
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