scholarly journals Resolving the heterogeneity of diaphragmatic mesenchyme: a novel mouse model of congenital diaphragmatic hernia

2021 ◽  
Vol 14 (1) ◽  
pp. dmm046797
Author(s):  
Louise Cleal ◽  
Sophie L. McHaffie ◽  
Martin Lee ◽  
Nick Hastie ◽  
Ofelia M. Martínez-Estrada ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Epithelial To Mesenchymal Transition ◽  
Wilms Tumor ◽  
Cell Types ◽  
Lineage Tracing ◽  
Developmental Defect ◽  
Mortality And Morbidity ◽  
Mesenchymal Transition ◽  
Expression Of Genes

ABSTRACTCongenital diaphragmatic hernia (CDH) is a relatively common developmental defect with considerable mortality and morbidity. Formation of the diaphragm is a complex process that involves several cell types, each with different developmental origins. Owing to this complexity, the aetiology of CDH is not well understood. The pleuroperitoneal folds (PPFs) and the posthepatic mesenchymal plate (PHMP) are transient structures that are essential during diaphragm development. Using several mouse models, including lineage tracing, we demonstrate the heterogeneous nature of the cells that make up the PPFs. The conditional deletion of Wilms tumor 1 homolog (Wt1) in the non-muscle mesenchyme of the PPFs results in CDH. We show that the fusion of the PPFs and the PHMP to form a continuous band of tissue involves movements of cells from both sources. The PPFs of mutant mice fail to fuse with the PHMP and exhibit increased RALDH2 (also known as ALDH1A2) expression. However, no changes in the expression of genes (including Snai1, Snai2, Cdh1 and Vim) implicated in epithelial-to-mesenchymal transition are observed. Additionally, the mutant PPFs lack migrating myoblasts and muscle connective tissue fibroblasts (TCF4+/GATA4+), suggesting possible interactions between these cell types. Our study demonstrates the importance of the non-muscle mesenchyme in development of the diaphragm.

scholarly journals The Impact of the Nephrotoxin Ochratoxin A on Human Renal Cells Studied by a Novel Co-Culture Model Is Influenced by the Presence of Fibroblasts

Toxins ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 219
Author(s):  
Gerald Schwerdt ◽  
Michael Kopf ◽  
Michael Gekle
Keyword(s):  
Ochratoxin A ◽  
Energy Homeostasis ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Types ◽  
Toxic Substances ◽  
Mesenchymal Transition ◽  
Expression Of Genes ◽  
Culture Model ◽  
Tubule Cells ◽  
The Impact

The kidney is threatened by a lot of potentially toxic substances. To study the influence of the nephrotoxin ochratoxin A (OTA) we established a cell co-culture model consisting of human renal proximal tubule cells and fibroblasts. We studied the effect of OTA on cell survival, the expression of genes and/or proteins related to cell death, extracellular matrix and energy homeostasis. OTA-induced necrosis was enhanced in both cell types in the presence of the respective other cell type, whereas OTA-induced apoptosis was independent therefrom. In fibroblasts, but not in tubule cells, a co-culture effect was visible concerning the expression of the cell-cycle-related protein p21. The expression of the epithelial-to-mesenchymal transition-indicating protein vimentin was independent from the culture-condition. The expression of the OTA-induced lncRNA WISP1-AS1 was enhanced in co-culture. OTA exposure led to alterations in the expression of genes related to energy metabolism with a glucose-mobilizing effect and a reduced expression of mitochondrial proteins. Together we demonstrate that the reaction of cells can be different in the presence of cells which naturally are close-by, thus enabling a cellular cross-talk. Therefore, to evaluate the toxicity of a substance, it would be an advantage to consider the use of co-cultures instead of mono-cultures.

scholarly journals Resolving the heterogeneity of diaphragmatic mesenchyme: a novel mouse model of congenital diaphragmatic hernia

2020 ◽  
Author(s):  
Louise Cleal ◽  
Ofelia Martinez-Estrada ◽  
You-Ying Chau
Keyword(s):  
Connective Tissue ◽  
Congenital Diaphragmatic Hernia ◽  
Mouse Models ◽  
Diaphragmatic Hernia ◽  
Cell Types ◽  
Mesenchymal Cells ◽  
Mutant Mice ◽  
Developmental Defect ◽  
Wilms Tumour ◽  
Continuous Band

AbstractCongenital diaphragmatic hernia (CDH) is a relatively common developmental defect with considerable mortality and morbidity. Diaphragm formation is a complex process, involving several cell types, each with different developmental origins. Due to this complexity, the aetiology of CDH is not well understood. The pleuroperitoneal folds (PPFs) and the post hepatic mesenchymal plate (PHMP) are transient structures that are essential during diaphragm development. Using several mouse models including lineage tracing, we demonstrate the heterogeneous nature of the cells that make up the PPFs. The conditional deletion of Wt1 (Wilms’ Tumour gene) in the non-muscle mesenchyme of the PPFs results in CDH. We show that the fusion of the PPFs and the PHMP to form a continuous band of tissue involves migration of cells from both sources. The PPFs of mutant mice fail to fuse with the PHMP and exhibit increased RALDH2 expression. However, no changes in the expression of genes implicated in epithelial-to-mesenchymal transition (EMT) are observed. Additionally, the mutant PPFs lack migrating myoblasts and muscle connective tissue fibroblasts (TCF4+/GATA4+), suggesting possible interactions between these cell types. Our study demonstrates the importance of the non-muscle mesenchyme in diaphragm development.Author SummaryCongenital diaphragmatic hernia (CDH) is a frequent developmental defect and it remains one of the most difficult problems of perinatology. The defect can be repaired by surgery but it is often associated with complications and total mortalities are still high (50-60%). The causes of CDH are largely unknown. Body cavity formation is a carefully regulated process, and diaphragm formation defines the thoracic and abdominal cavities. Connective tissue and muscle fibres are the known major players involved in diaphragm formation. Our current study emphasises another player, the mesenchymal cells. We manipulate the expression of an important developmental regulator, Wt1 (Wilms’ tumour gene), in mesenchymal cells in a tissue specific manner using transgenic mouse models. We found that mutant mice can survive till birth, develop diaphragmatic hernia, and die shortly after birth. Ablating Wt1 in the mesenchymal cells leads to ceased movement, and the failure to form a continuous band of tissue. In our model, disruption of mesenchymal cell movement leads to the attenuation of migration of connective tissue fibroblasts and myoblasts, suggesting possible interactions between these cell types.

scholarly journals Ultrasound, Echocardiography, MRI, and Genetic Analysis of a Fetus with Congenital Diaphragmatic Hernia and Partial 11q Trisomy

2017 ◽  
Vol 2017 ◽  
pp. 1-4
Author(s):  
Yolanda Fernández-Perea ◽  
Lutgardo García-Díaz ◽  
Javier Sánchez ◽  
Guillermo Antiñolo ◽  
Salud Borrego
Keyword(s):  
Prenatal Diagnosis ◽  
Genetic Analysis ◽  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
De Novo ◽  
Partial Trisomy ◽  
Congenital Defects ◽  
Developmental Defect ◽  
Chromosome 11 ◽  
Mortality And Morbidity

Congenital diaphragmatic hernia (CDH) is a serious birth defect with a significant mortality and morbidity. The current and constant progress in ultrasound techniques has led to the improvement of the prenatal diagnosis of this malformation. CDH is a developmental defect whose etiology is heterogeneous and takes place when the pleuroperitoneal folds and septum transversum fail to converge and fuse. Survival depends on the extent of pulmonary hypoplasia and the disease may be potentially worsened by the presence of added congenital defects. 40% of CDH cases are associated with at least one additional anomaly. The ultrasound diagnosis is established with essential signs: loss of uniform echogenicity of lungs and marked mediastinal shift. We report the case of a fetus with isolated CDH diagnosed at 21 weeks of gestation by ultrasound and confirmed by RMI, whose genetic analysis of amniotic fluid cells identified a de novo partial trisomy of the long arm of chromosome 11. Different genetic causes have been associated with CDH. Moreover, it is expectable that the use of new techniques for prenatal diagnosis will reveal novel CNVs associated with CDH and will help us to estimate the recurrence risk for this defect as well as for other associated anomalies.

scholarly journals Increased vimentin in human α- and β-cells in type 2 diabetes

2017 ◽  
Vol 233 (3) ◽  
pp. 217-227 ◽  
Author(s):  
Maaike M Roefs ◽  
Françoise Carlotti ◽  
Katherine Jones ◽  
Hannah Wills ◽  
Alexander Hamilton ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Epithelial To Mesenchymal Transition ◽  
Islet Cells ◽  
Cell Types ◽  
Β Cells ◽  
Β Cell ◽  
Mesenchymal Transition ◽  
Cell Expression

Type 2 diabetes (T2DM) is associated with pancreatic islet dysfunction. Loss of β-cell identity has been implicated via dedifferentiation or conversion to other pancreatic endocrine cell types. How these transitions contribute to the onset and progression of T2DM in vivo is unknown. The aims of this study were to determine the degree of epithelial-to-mesenchymal transition occurring in α and β cells in vivo and to relate this to diabetes-associated (patho)physiological conditions. The proportion of islet cells expressing the mesenchymal marker vimentin was determined by immunohistochemistry and quantitative morphometry in specimens of pancreas from human donors with T2DM (n = 28) and without diabetes (ND, n = 38) and in non-human primates at different stages of the diabetic syndrome: normoglycaemic (ND, n = 4), obese, hyperinsulinaemic (HI, n = 4) and hyperglycaemic (DM, n = 8). Vimentin co-localised more frequently with glucagon (α-cells) than with insulin (β-cells) in the human ND group (1.43% total α-cells, 0.98% total β-cells, median; P < 0.05); these proportions were higher in T2DM than ND (median 4.53% α-, 2.53% β-cells; P < 0.05). Vimentin-positive β-cells were not apoptotic, had reduced expression of Nkx6.1 and Pdx1, and were not associated with islet amyloidosis or with bihormonal expression (insulin + glucagon). In non-human primates, vimentin-positive β-cell proportion was larger in the diabetic than the ND group (6.85 vs 0.50%, medians respectively, P < 0.05), but was similar in ND and HI groups. In conclusion, islet cell expression of vimentin indicates a degree of plasticity and dedifferentiation with potential loss of cellular identity in diabetes. This could contribute to α- and β-cell dysfunction in T2DM.

scholarly journals Specific Gene- and MicroRNA-Expression Pattern Contributes to the Epithelial to Mesenchymal Transition in a Rat Model of Experimental Colitis

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Éva Boros ◽  
Marianna Csatári ◽  
Csaba Varga ◽  
Balázs Bálint ◽  
István Nagy
Keyword(s):  
Expression Pattern ◽  
Rat Model ◽  
Epithelial To Mesenchymal Transition ◽  
Experimental Colitis ◽  
Microrna Expression ◽  
Specific Gene ◽  
Mesenchymal Transition ◽  
Expression Of Genes ◽  
Epithelial Marker ◽  
Male Wistar Rats

The aim of this study was to determine the gene- and microRNA-expression profile contributing to epithelial to mesenchymal transition in a rat model of experimental colitis. For this, inflammation was induced by injecting 2,4,6-trinitrobenzene sulphonic acid to the colon of male Wistar rats. Samples were taken from both inflamed and uninflamed regions of the same colon, total RNA was isolated, and the mRNA and microRNA expressions were monitored. We have determined that the expression of genes responsible for inducing mesenchymal phenotype, such as Egr1, Fgf2, Fgf7, Jak2, Notch2, Hif1α, Zeb2, Mmp9, Lox, and Vim, was all significantly induced in the inflamed regions of the affected colons while the epithelial marker E-cadherin (Cdh1) was downregulated. In contrast, the expression of microRNAs miR-192, miR-143, miR-375, miR-30a, miR-107, and miR-200b responsible for the regulation of the above mentioned genes was significantly downregulated in inflamed colon. Importantly, we detected moderate induction in the expression of five out of six tested microRNAs in the uninflamed regions. In summary, we identified numerous interacting genes and microRNAs with mutually exclusive expression pattern in inflamed regions of colitis-induced rats. These findings suggest that—among others—an important step in the epithelial to mesenchymal transition in experimental colitis is the dysregulated microRNA expression.

scholarly journals Perinatal stabilisation of infants born with congenital diaphragmatic hernia: a review of current concepts

2020 ◽  
Vol 105 (4) ◽  
pp. 449-454
Author(s):  
Emily J J Horn-Oudshoorn ◽  
Ronny Knol ◽  
Arjan B Te Pas ◽  
Stuart B Hooper ◽  
Suzan C M Cochius-den Otter ◽  
...  
Keyword(s):  
Congenital Diaphragmatic Hernia ◽  
Diaphragmatic Hernia ◽  
Management Strategies ◽  
Fetal Surgery ◽  
Adverse Outcomes ◽  
Delivery Room ◽  
Treatment Modalities ◽  
Mortality And Morbidity ◽  
Early Predictors ◽  
Stabilisation Period

Congenital diaphragmatic hernia (CDH) is associated with high mortality rates and significant pulmonary morbidity, mainly due to disrupted lung development related to herniation of abdominal organs into the chest. Pulmonary hypertension is a major contributor to both mortality and morbidity, however, treatment modalities are limited. Novel prenatal and postnatal interventions, such as fetal surgery and medical treatments, are currently under investigation. Until now, the perinatal stabilisation period immediately after birth has been relatively overlooked, although optimising support in these early stages may be vital in improving outcomes. Moreover, physiological parameters obtained from the perinatal stabilisation period could serve as early predictors of adverse outcomes, thereby facilitating both prevention and early treatment of these conditions. In this review, we focus on the perinatal stabilisation period by discussing the current delivery room guidelines in infants born with CDH, the physiological changes occurring during the fetal-to-neonatal transition in CDH, novel delivery room strategies and early predictors of adverse outcomes. The combination of improvements in the perinatal stabilisation period and early prediction of adverse outcomes may mitigate the need for specific postnatal management strategies.

scholarly journals Interplay among SNAIL Transcription Factor, MicroRNAs, Long Non-Coding RNAs, and Circular RNAs in the Regulation of Tumor Growth and Metastasis

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 209 ◽  
Author(s):  
Klaudia Skrzypek ◽  
Marcin Majka
Keyword(s):  
Transcription Factor ◽  
Tumor Growth ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Metabolism ◽  
Circular Rnas ◽  
Mesenchymal Transition ◽  
Expression Of Genes ◽  
Non Coding Rnas ◽  
Tumor Growth And Metastasis ◽  
Novel Therapeutic Strategies

SNAIL (SNAI1) is a zinc finger transcription factor that binds to E-box sequences and regulates the expression of genes. It usually acts as a gene repressor, but it may also activate the expression of genes. SNAIL plays a key role in the regulation of epithelial to mesenchymal transition, which is the main mechanism responsible for the progression and metastasis of epithelial tumors. Nevertheless, it also regulates different processes that are responsible for tumor growth, such as the activity of cancer stem cells, the control of cell metabolism, and the regulation of differentiation. Different proteins and microRNAs may regulate the SNAIL level, and SNAIL may be an important regulator of microRNA expression as well. The interplay among SNAIL, microRNAs, long non-coding RNAs, and circular RNAs is a key event in the regulation of tumor growth and metastasis. This review for the first time discusses different types of regulation between SNAIL and non-coding RNAs with a focus on feedback loops and the role of competitive RNA. Understanding these mechanisms may help develop novel therapeutic strategies against cancer based on microRNAs.

Mechanisms of Neural Crest Migration

2018 ◽  
Vol 52 (1) ◽  
pp. 43-63 ◽  
Author(s):  
András Szabó ◽  
Roberto Mayor
Keyword(s):  
Neural Crest ◽  
Cell Population ◽  
Epithelial To Mesenchymal Transition ◽  
Neural Crest Cells ◽  
Cell Types ◽  
Embryonic Cell ◽  
Mesenchymal Transition ◽  
Chain Migration ◽  
Mass Migration ◽  
Neural Crest Migration

Neural crest cells are a transient embryonic cell population that migrate collectively to various locations throughout the embryo to contribute a number of cell types to several organs. After induction, the neural crest delaminates and undergoes an epithelial-to-mesenchymal transition before migrating through intricate yet characteristic paths. The neural crest exhibits a variety of migratory behaviors ranging from sheet-like mass migration in the cephalic regions to chain migration in the trunk. During their journey, neural crest cells rely on a range of signals both from their environment and within the migrating population for navigating through the embryo as a collective. Here we review these interactions and mechanisms, including chemotactic cues of neural crest cells’ migration.

scholarly journals Roles of the CXCL8-CXCR1/2 Axis in the Tumor Microenvironment and Immunotherapy

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 137
Author(s):  
Zhi-Jian Han ◽  
Yang-Bing Li ◽  
Lu-Xi Yang ◽  
Hui-Juan Cheng ◽  
Xin Liu ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Progression ◽  
Immune Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Checkpoint Inhibitors ◽  
Lymphatic Vessels ◽  
Cell Types ◽  
Mesenchymal Transition ◽  
Development Of Resistance ◽  
Immunosuppressive Cells

In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

scholarly journals Cell transformation disrupts the efficiency of chromosome segregation through microtubule detyrosination

2018 ◽  
Author(s):  
Virginia Silió ◽  
Jonathan B. Millar ◽  
Andrew D. McAinsh
Keyword(s):  
Chromosome Segregation ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Transformation ◽  
Retinal Pigment ◽  
Mesenchymal Cell ◽  
Cell Types ◽  
Retinal Pigment Epithelial Cells ◽  
Mesenchymal Transition ◽  
Carboxypeptidase Inhibitor ◽  
Different Cell Types

The general principles of chromosome segregation are highly conserved throughout eukaryotic evolution. However, it is unknown whether there are differences in spindle or kinetochore composition or architecture which influence the efficiency chromosome segregation in different cell types. Here we show that the transition of human retinal pigment epithelial cells to a mesenchymal phenotype causes a stabilisation of kinetochore-microtubule attachments and an increase in the frequency of chromosome mis-segregation, due to inefficient error-correction, during mitosis. We find that this is caused by microtubule detyrosination during the epithelial-to-mesenchymal transition and that parthenolide, a tubulin carboxypeptidase inhibitor, efficiently reverts mes-enchymal cells to the epithelial mode of chromosome segregation. We propose that reprogramming the post-translational modifications of the mitotic spindle decreases mitotic fidelity and may contribute to CIN in mesenchymal cell populations during tumorigenesis.

Sign in / Sign up

Export Citation Format

Share Document