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PURPOSE: Children and young adults with neuromuscular disorders have a high incidence of both spine and hip deformities. The aim of this study was to evaluate the outcome of either primary scoliosis or hip surgery in children and young adults with neuromuscular disorders. METHODS: A retrospective study was conducted on all children and young adults with neuromuscular-related synchronous hip subluxation/dislocation and scoliosis undergoing hip or scoliosis surgery in our institution between 2012 and 2021 with a minimum follow-up of 24 months. Demographic and operative data were collected; radiological parameters were measured preoperatively and postoperatively at final follow-up. RESULTS: Forty neuromuscular patients with synchronous hip displacement and scoliosis were included. Twenty patients with an average age of10.2 years had hip correction surgery performed primarily, with a mean follow-up of 54.9 (24-96) months. The other 20 patients with an average age of 12.4 years had scoliosis correction first, with a mean follow-up of 40 (24-60) months. In the "Hip first" group, pelvic obliquity, hip MP and Cobb angle were 16.8°, 71%, and 49°, respectively. At final follow-up, the mean pelvic obliquity and Cobb angles significantly progressed to 27.2° (p = 0.003) and 82.2° (p = 0.001), respectively. Eighteen patients (90%) required scoliosis correction after the hip surgery. In the "Scoliosis first" group, the mean pelvic obliquity, hip MP and Cobb angle were 21.2°, 49% and 65.5°, respectively. At final follow-up, both pelvic obliquity and Cobb angle significantly improved to 8.44° (p = 0.002) and 23.4° (p = 0.001), respectively. In 11/20 (55%) patients, the hip MP had significantly increased following the spinal surgery to 62% (p = 0.001), but only 5/20 (25%) patients underwent hip surgery after scoliosis correction. CONCLUSION: In neuromuscular patients presenting with synchronous hip displacement and scoliosis deformity, corrective scoliosis surgery is associated with a significant correction of pelvic obliquity and lower rates of secondary hip surgery. On the other hand, primary hip surgery does not reduce the risk of pelvic obliquity and scoliosis deformity progression.
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Enfermedades Neuromusculares , Escoliosis , Humanos , Escoliosis/cirugía , Escoliosis/diagnóstico por imagen , Estudios Retrospectivos , Femenino , Niño , Masculino , Enfermedades Neuromusculares/complicaciones , Enfermedades Neuromusculares/cirugía , Adolescente , Resultado del Tratamiento , Adulto Joven , Luxación de la Cadera/cirugía , Luxación de la Cadera/etiología , Estudios de Seguimiento , Cadera/diagnóstico por imagen , Cadera/cirugíaRESUMEN
INTRODUCTION: The increasing socioeconomic need for optimal treatment of hip fractures in combination with the high diversity of available implants has raised numerous biomechanical questions. This study aims to provide a comprehensive overview of biomechanical research on the treatment of intertrochanteric fractures using cephalomedullary devices. METHODS: Following the PRISMA-P guidelines, a systematic literature search was performed on 31.12.2022. The databases PubMed/MEDLINE and Web of Science were searched. Scientific papers published between 01.01.2000 - 31.12.2022 were included when they reported data on implant properties related to the biomechanical stability for intertrochanteric fractures. Data extraction was undertaken using a synthesis approach, gathering data on criteria of implants, sample size, fracture type, bone material, and study results. RESULTS: The initial search identified a total of 1459 research papers, out of which forty-three papers were considered for final analysis. Due to the heterogeneous methods and parameters used in the included studies, meta-analysis was not feasible. A comprehensive assessment of implant characteristics and outcome parameters was conducted through biomechanical analysis. Various factors such as proximal and distal locking, nail diameter and length, fracture model, and bone material were thoroughly evaluated. CONCLUSION: This scoping review highlights the need for standardization in biomechanical studies on intertrochanteric fractures to ensure reliable and comparable results. Strategies such as avoiding varus, maintaining a sufficient tip-apex-distance, cement augmentation, and optimizing lesser trochanteric osteosynthesis enhance construct stability. Synthetic alternatives may offer advantages over cadaveric bone. Further research and meta-analyses are required to establish standardized protocols and enhance reliability.
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Fijación Intramedular de Fracturas , Fracturas de Cadera , Humanos , Clavos Ortopédicos , Tornillos Óseos , Fijación Intramedular de Fracturas/métodos , Uñas , Reproducibilidad de los Resultados , Revisiones Sistemáticas como Asunto , Metaanálisis como Asunto , Fracturas de Cadera/cirugía , Resultado del TratamientoRESUMEN
Bones normally function to provide both mechanical and locomotion supports in the body. They are highly specialized connective tissues that are characterized by mineralized extracellular components, which provide both rigidity and strength to bones. Stem cells hold great potentials for both the repair and regeneration of different tissue types, including bone tissues. The future use of stem cell therapy is promising for developing regenerative medicine approaches to treat disorders and diseases in a wide range of tissues such as cartilages and bones. Data have been accumulated recently on the application of different stem cell types in bone repair, regeneration, and disorders. In this article, we briefly describe the bone structure and review research progress and recently accumulated data on stem cell differentiation into osteoblasts as well as discuss the contributions of stem cell types to bone and cartilage repair, regeneration, and disease.
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Células Madre Mesenquimatosas , Ingeniería de Tejidos , Humanos , Células Madre , Medicina Regenerativa , Cartílago , Diferenciación Celular , Regeneración ÓseaRESUMEN
Histones form chromatin and play a key role in the regulation of gene expression. As an epigenetic information form, histone modifications such as methylation, phosphorylation, acetylation, and ubiquitination are closely related to the regulation of genes. In the last two decades, cancer scientists discovered that some histone modifications, including acetylation and methylation, are perturbed in cancer diseases. Recurrent histone mutations, which hinder histone methylation and are implicated in oncogenesis, are recently identified in several cancer disease and called oncohistones. Well-known oncohistones, with mutations on both H3.1 and H3.3, include H3K36M in chondroblastoma, H3K27M in glioma, and H3G34 mutations that exist in bone cancers and gliomas. Oncohistone expression can lead to epigenome/transcriptome reprogramming and eventually to oncogenesis. The H3K27M, H3G34V/R, and H3K36M histone mutations can lead to the substitution of amino acid(s) at or near a lysine residue, which is a methylation target. H3K27M characteristically exists in diffuse intrinsic pontine glioma (pediatric DIPG), and its expression can cause a global decrease of the methylation of histone at the lysine residue. Uncovering the molecular mechanisms of H3K27M-driven tumorigenesis has recently led to the identification of some potential therapeutic targets in diffuse intrinsic pontine glioma. In this chapter, we will review and summarize recent studies on the H3K27M-driven tumorigenic mechanisms and properties and the role of H3.1K27M and H3.3K27M oncohistones in brain tumors.
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Neoplasias del Tronco Encefálico , Glioma , Histonas/genética , Mutación , Neoplasias del Tronco Encefálico/genética , Cromatina , Glioma/genética , HumanosRESUMEN
INTRODUCTION: Skeletal involvement in children with Langerhans cell histiocytosis (LCH) is a common feature of the disease. Several options for the treatment of these skeletal lesions have been reported. We describe our experience in the treatment of skeletal involvement of LCH in this retrospective case series study, entailing anatomic distribution, pattern of healing, skeletal deformities, and functional outcome of skeletal LCH. METHODS: A retrospective analysis was conducted for patients diagnosed with LCH and having skeletal lesions in the period between 2007 and 2015. Out of a total of 229 cases, 191 (83.4%) had skeletal involvement. Bone healing was divided into partial and complete based on the size of lesion and cortical changes in plain radiograph. Skeletal deformities were serially measured. Time to pain control, resumption of weight bearing, and the final functional status of the patient were reviewed. RESULTS: The mean age at presentation was 4.4 years (3 m-14.8 y) and the mean follow-up period was 53.3 months (0.2-120.7). After screening of skeletal and extra-skeletal lesions, 59 patients (31%) had M-S (Multisystem) LCH and 132 (69%) had S-S (Single system) LCH. Unifocal bone lesions were found in 81 (42.5%) patients, and multifocal bone lesions in 110 patients (57.5%). Single or multiple bone lesions were found in the craniofacial bones in 152 patients (79.5%), femur in 19 patients, (10%), ribs in 18 patients (9.4%), spine in 15 patients (8.1%), pelvis in 14 patients (7.3%), scapula in 8 patients (4.1%), humerus in 6 (3.1%), clavicle in 6 patients (3.1%), tibia in 3 patients (1.5%), radius in 3 patients (1.5%), and the ulna in 2 patients (1%) patients. No lesions were found in the fibula, hand, or foot. Out of all skeletal lesions, 179 (93.7%) patients were treated either medically or conservatively and 12 patients (6.2%) were treated surgically. The mean time to complete healing was 5.2 months (2-12). Skeletal complications included: pathologic fractures (9 vertebra plana, 5 long bone, 1 iliac bone), deformities (9 thoracolumbar kyphosis, 2 cervical spine subluxations, 2 coxa vara deformity of the proximal femur and one flattening of iliac bone). CONCLUSION: Non-operative treatment can lead to adequate bone healing in few months period. Partial or complete remodeling of bone deformities can be observed without surgical correction. However, surgical intervention might be indicated when cervical spine affection may lead to instability and subsequent neurological affection. Functional impairment is rarely caused by skeletal lesions in LCH.
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Idiopathic pulmonary fibrosis (IPF) is an example of interstitial lung diseases that is characterized by chronic, progressive, and fibrotic lung injuries. During lung fibrosis, normal healthy lung tissues are replaced by remarkably destroyed alveolar architecture and altered extracellular cell matrix. These changes eventually cause severe disruption of the tightly-controlled gas exchange process and reduction of lung compliance that ultimately lead to both respiratory failure and death. In the last decade, progress has been made toward understanding the pathogenesis of pulmonary fibrosis, and two novel disease-modifying therapies were approved. However, finding more effective treatments for pulmonary fibrosis is still a challenge, with its incidence continues to increase globally, which is associated with significantly high mortality, morbidity and economical healthcare burden. Different stem cell types have recently emerged as a promising therapy for human diseases, including lung fibrosis, with numerous studies on the identification, characterization, proliferation and differentiation of stem cells. A large body of both basic and pre-clinical research on stem cells has been recently translated to patient care worldwide. Herein, we review recent advances in our understanding of the pathophysiology of IPF, and types of cells used in IPF cell-based therapies, including alveolar and mixed lung epithelial cells, different stem cell types (MSCs, ADSCs, IPSCs etc.), endogenous lung tissue-specific stem cells, and circulating endothelial progenitors (EPCs). We also discuss recent studies on the applications of these cells in IPF therapy and their delivery routes, effective doses for cell therapy, and timing of delivery. Finally, we discuss attractive recent and current clinical trials conducted on cell-based therapy for IPF.
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The exploration of stem and progenitor cells holds promise for advancing our understanding of the biology of tissue repair and regeneration mechanisms after injury. This will also help in the future use of stem cell therapy for the development of regenerative medicine approaches for the treatment of different tissue-species defects or disorders such as bone, cartilages, and tooth defects or disorders. Bone is a specialized connective tissue, with mineralized extracellular components that provide bones with both strength and rigidity, and thus enable bones to function in body mechanical supports and necessary locomotion process. New insights have been added to the use of different types of stem cells in bone and tooth defects over the last few years. In this concise review, we briefly describe bone structure as well as summarize recent research progress and accumulated information regarding the osteogenic differentiation of stem cells, as well as stem cell contributions to bone repair/regeneration, bone defects or disorders, and both restoration and regeneration of bones and cartilages. We also discuss advances in the osteogenic differentiation and bone regeneration of dental and periodontal stem cells as well as in stem cell contributions to dentine regeneration and tooth engineering.
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Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Osteogénesis/fisiología , Medicina Regenerativa/métodos , Trasplante de Células Madre/métodos , Ingeniería de Tejidos/métodos , Regeneración Ósea , Huesos/citología , Diferenciación Celular , Humanos , Células Madre , Diente/citologíaRESUMEN
New insights have been added to identification, behavior and cellular properties of embryonic and tissue-specific stem cells over the last few years. The modes of stem cell division, asymmetric vs. symmetric, are tightly regulated during development and regeneration. The proper choice of a stem cell to divide asymmetrically or symmetrically has great consequences for development and disease because inappropriate asymmetric division disrupts organ morphogenesis, whereas uncontrolled symmetric division induces tumorigenesis. Therefore, understanding the behavior of lung stem cells could identify innovative solutions for restoring normal morphogenesis and/or regeneration of different organs. In this concise review, we describe recent studies in our laboratory about the mode of division of lung epithelial stem cells. We also compare asymmetric cell division (ACD) in the lung stem cells with other tissues in different organisms.
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The Eya1 gene encodes a transcriptional co-activator that acts with Six1 to control the development of different organs. However, Six1-Eya1 interactions and functional roles in mesenchymal cell proliferation and differentiation as well as alveolarization during the saccular stage of lung development are still unknown. Herein, we provide the first evidence that Six1 and Eya1 act together to regulate mesenchymal development as well as alveolarization during the saccular phase of lung morphogenesis. Deletion of either or both Six1 and Eya1 genes results in a severe saccular phenotype, including defects of mesenchymal cell development and remodeling of the distal lung septae and arteries. Mutant lung histology at the saccular phase shows mesenchymal and saccular wall thickening, and abnormal proliferation of α-smooth muscle actin-positive cells, as well as increased mesenchymal/fibroblast cell differentiation, which become more sever when deleting both genes. Our study indicates that SHH but not TGF-ß signaling pathway is a central mediator for the histologic alterations described in the saccular phenotype of Eya1(-/-) or Six1(-/-) lungs. Indeed, genetic reduction of SHH activity in vivo or inhibition of its activity in vitro substantially rescues lung mesenchymal and alveolar phenotype of mutant mice at the saccular phase. These findings uncover novel functions for Six1-Eya1-SHH pathway during the saccular phase of lung morphogenesis, providing a conceptual framework for future mechanistic and translational studies in this area.
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Proteínas de Homeodominio/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Pulmón/embriología , Pulmón/metabolismo , Morfogénesis , Proteínas Nucleares/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Animales , Capilares/efectos de los fármacos , Capilares/crecimiento & desarrollo , Diferenciación Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Proteínas Hedgehog/metabolismo , Heterocigoto , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Pulmón/irrigación sanguínea , Pulmón/citología , Mesodermo/citología , Mesodermo/efectos de los fármacos , Mesodermo/metabolismo , Ratones , Ratones Mutantes , Modelos Biológicos , Morfogénesis/efectos de los fármacos , Proteínas Nucleares/deficiencia , Fenotipo , Proteínas Tirosina Fosfatasas/deficiencia , Alveolos Pulmonares/citología , Alveolos Pulmonares/efectos de los fármacos , Alveolos Pulmonares/embriología , Alveolos Pulmonares/metabolismo , Transducción de Señal/efectos de los fármacos , Alcaloides de Veratrum/farmacologíaRESUMEN
Little is known about the regulatory mechanisms underlying lung epithelial tight junction (TJ) assembly, which is inextricably linked to the preservation of epithelial polarity, and is highly coordinated by proteins that regulate epithelial cell polarity, such as aPKCζ. We recently reported that Eya1 phosphatase functions through aPKCζ-Notch1 signaling to control cell polarity in the lung epithelium. Here, we have extended these observations to TJ formation to demonstrate that Eya1 is crucial for the maintenance of TJ protein assembly in the lung epithelium, probably by controlling aPKCζ phosphorylation levels, aPKCζ-mediated TJ protein phosphorylation and Notch1-Cdc42 activity. Thus, TJs are disassembled after interfering with Eya1 function in vivo or during calcium-induced TJ assembly in vitro. These effects are reversed by reintroduction of wild-type Eya1 or partially inhibiting aPKCζ in Eya1siRNA cells. Moreover, genetic activation of Notch1 rescues Eya1(-/-) lung epithelial TJ defects. These findings uncover novel functions for the Eya1-aPKCζ-Notch1-Cdc42 pathway as a crucial regulatory mechanism of TJ assembly and polarity of the lung epithelium, providing a conceptual framework for future mechanistic and translational studies in this area.
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Epitelio/enzimología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Pulmón/citología , Pulmón/enzimología , Proteínas Nucleares/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Uniones Estrechas/metabolismo , Animales , Calcio/metabolismo , Membrana Celular/metabolismo , Activación Enzimática , Células Epiteliales/citología , Células Epiteliales/enzimología , Epitelio/embriología , Femenino , Eliminación de Gen , Inmunoprecipitación , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Pulmón/embriología , Ratones , Proteínas Nucleares/deficiencia , Fosforilación , Proteína Quinasa C/metabolismo , Transporte de Proteínas , Proteínas Tirosina Fosfatasas/deficiencia , Receptor Notch1/metabolismo , Transducción de Señal , Activación Transcripcional , Proteína de Unión al GTP cdc42/metabolismoRESUMEN
Proper balance between self-renewal and differentiation of lung-specific progenitors is absolutely required for normal lung morphogenesis/regeneration. Therefore, understanding the behavior of lung epithelial stem/progenitor cells could identify innovative solutions for restoring normal lung morphogenesis and/or regeneration. The Notch inhibitor Numb is a key determinant of asymmetric or symmetric cell division and hence cell fate. Yet Numb proximal-distal expression pattern and symmetric versus asymmetric division are uncharacterized during lung epithelial development. Herein, the authors find that the cell fate determinant Numb is highly expressed and asymmetrically distributed at the apical side of distal epithelial progenitors and segregated to one daughter cell in most mitotic cells. Knocking down Numb in MLE15 epithelial cells significantly increased the number of cells expressing the progenitor cell markers Sox9/Id2. Furthermore, cadherin hole analysis revealed that most distal epithelial stem/progenitor cells in embryonic lungs divide asymmetrically; with their cleavage, planes are predicted to bypass the cadherin hole, resulting in asymmetric distribution of the cadherin hole to the daughter cells. These novel findings provide evidence for asymmetric cell division in distal epithelial stem/progenitor cells of embryonic lungs and a framework for future translationally oriented studies in this area.
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Pulmón/citología , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Mucosa Respiratoria/citología , Células Madre/citología , Animales , División Celular , Línea Celular , Técnicas de Silenciamiento del Gen , Pulmón/embriología , Pulmón/metabolismo , Proteínas de la Membrana/genética , Ratones , Proteínas del Tejido Nervioso/genética , Mucosa Respiratoria/embriología , Mucosa Respiratoria/metabolismoRESUMEN
Six1 is a member of the six-homeodomain family of transcription factors. Six1 is expressed in multiple embryonic cell types and plays important roles in proliferation, differentiation and survival of precursor cells of different organs, yet its function during lung development was hitherto unknown. Herein we show that Six1(-/-) lungs are severely hypoplastic with greatly reduced epithelial branching and increased mesenchymal cellularity. Six1 is expressed at the distal epithelial tips of branching tubules as well as in the surrounding distal mesenchyme. Six1(-/-) lung epithelial cells show increased expression of differentiation markers, but loss of progenitor cell markers. Six1 overexpression in MLE15 lung epithelial cells in vitro inhibited cell differentiation, but increases the expression of progenitor cell markers. In addition, Six1(-/-) embryos and newborn mice exhibit mesenchymal overproliferation, decreased Fgf10 expression and severe defects in the smooth muscle component of the bronchi and major pulmonary vessels. These defects lead to rupture of major vessels in mutant lungs after birth. Treatment of Six1(-/-) epithelial explants in culture with recombinant Fgf10 protein restores epithelial branching. As Shh expression is abnormally increased in Six1(-/-) lungs, we also treated mutant mesenchymal explants with recombinant Shh protein and found that these explants were competent to respond to Shh and continued to grow in culture. Furthermore, inhibition of Shh signaling with cyclopamine stimulated Six1(-/-) lungs to grow and branch in culture. This study provides the first evidence for the requirement of Six1 in coordinating Shh-Fgf10 signaling in embryonic lung to ensure proper levels of proliferation and differentiation along the proximodistal axis of epithelial, mesenchymal and endothelial cells. These findings uncover novel and essential functions for Six1 as a critical coordinator of Shh-Fgf10 signaling during embryonic lung development. We propose that Six1 is hence critical for coordination of proper lung epithelial, mesenchymal and vascular development.
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Proteínas de Homeodominio/fisiología , Pulmón/embriología , Actinas/metabolismo , Animales , Diferenciación Celular , Proliferación Celular , Células Madre Embrionarias/citología , Factor 10 de Crecimiento de Fibroblastos/genética , Factor 10 de Crecimiento de Fibroblastos/farmacología , Factor 10 de Crecimiento de Fibroblastos/fisiología , Regulación del Desarrollo de la Expresión Génica , Proteínas Hedgehog/antagonistas & inhibidores , Proteínas Hedgehog/farmacología , Proteínas Hedgehog/fisiología , Proteínas de Homeodominio/genética , Pulmón/anomalías , Pulmón/irrigación sanguínea , Pulmón/crecimiento & desarrollo , Mesodermo/embriología , Mesodermo/crecimiento & desarrollo , Mesodermo/metabolismo , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Ratones Transgénicos , Morfogénesis/efectos de los fármacos , Morfogénesis/genética , Morfogénesis/fisiología , Miocitos del Músculo Liso/citología , Mucosa Respiratoria/embriología , Mucosa Respiratoria/crecimiento & desarrollo , Mucosa Respiratoria/metabolismo , Transducción de Señal/efectos de los fármacos , Alcaloides de Veratrum/farmacologíaRESUMEN
Cell polarity, mitotic spindle orientation and asymmetric division play a crucial role in the self-renewal/differentiation of epithelial cells, yet little is known about these processes and the molecular programs that control them in embryonic lung distal epithelium. Herein, we provide the first evidence that embryonic lung distal epithelium is polarized with characteristic perpendicular cell divisions. Consistent with these findings, spindle orientation-regulatory proteins Insc, LGN (Gpsm2) and NuMA, and the cell fate determinant Numb are asymmetrically localized in embryonic lung distal epithelium. Interfering with the function of these proteins in vitro randomizes spindle orientation and changes cell fate. We further show that Eya1 protein regulates cell polarity, spindle orientation and the localization of Numb, which inhibits Notch signaling. Hence, Eya1 promotes both perpendicular division as well as Numb asymmetric segregation to one daughter in mitotic distal lung epithelium, probably by controlling aPKCζ phosphorylation. Thus, epithelial cell polarity and mitotic spindle orientation are defective after interfering with Eya1 function in vivo or in vitro. In addition, in Eya1(-/-) lungs, perpendicular division is not maintained and Numb is segregated to both daughter cells in mitotic epithelial cells, leading to inactivation of Notch signaling. As Notch signaling promotes progenitor cell identity at the expense of differentiated cell phenotypes, we test whether genetic activation of Notch could rescue the Eya1(-/-) lung phenotype, which is characterized by loss of epithelial progenitors, increased epithelial differentiation but reduced branching. Indeed, genetic activation of Notch partially rescues Eya1(-/-) lung epithelial defects. These findings uncover novel functions for Eya1 as a crucial regulator of the complex behavior of distal embryonic lung epithelium.
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Diferenciación Celular/fisiología , Polaridad Celular/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Pulmón/embriología , Proteínas Nucleares/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Receptores Notch/metabolismo , Transducción de Señal/fisiología , Huso Acromático/metabolismo , Animales , Western Blotting , Proteínas de Ciclo Celular , Epitelio/embriología , Epitelio/metabolismo , Inmunoprecipitación , Péptidos y Proteínas de Señalización Intracelular/genética , Pulmón/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Transgénicos , Mitosis/fisiología , Morfogénesis/fisiología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas Nucleares/genética , Fosforilación/fisiología , Proteínas Tirosina Fosfatasas/genética , Receptores Notch/genética , Huso Acromático/genéticaRESUMEN
The proper level of proliferation and differentiation along the proximodistal axis is crucial for lung organogenesis. Elucidation of the factors that control these processes will therefore provide important insights into embryonic lung development and regeneration. Eya1 is a transcription factor/protein phosphatase that regulates cell lineage specification and proliferation. Yet its functions during lung development are unknown. In this paper we show that Eya1(-/-) lungs are severely hypoplastic with reduced epithelial branching and increased mesenchymal cellularity. Eya1 is expressed at the distal epithelial tips of branching tubules as well as in the surrounding distal mesenchyme. Eya1(-/-) lung epithelial cells show loss of progenitor cell markers with increased expression of differentiation markers and cell cycle exit. In addition, Eya1(-/-) embryos and newborn mice exhibit severe defects in the smooth muscle component of the bronchi and major pulmonary vessels with decreased Fgf10 expression. These defects lead to rupture of the major vessels and hemorrhage into the lungs after birth. Treatment of Eya1(-/-) epithelial explants in culture with recombinant Fgf10 stimulates epithelial branching. Since Shh expression and activity are abnormally increased in Eya1(-/-) lungs, we tested whether genetically lowering Shh activity could rescue the Eya1(-/-) lung phenotype. Indeed, genetic reduction of Shh partially rescues Eya1(-/-) lung defects while restoring Fgf10 expression. This study provides the first evidence that Eya1 regulates Shh signaling in embryonic lung, thus ensuring the proper level of proliferation and differentiation along the proximodistal axis of epithelial, mesenchymal and endothelial cells. These findings uncover novel functions for Eya1 as a critical upstream coordinator of Shh-Fgf10 signaling during embryonic lung development. We conclude, therefore, that Eya1 function is critical for proper coordination of lung epithelial, mesenchymal and vascular development.
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Vasos Sanguíneos/embriología , Péptidos y Proteínas de Señalización Intracelular/genética , Pulmón/embriología , Pulmón/enzimología , Mesodermo/embriología , Morfogénesis/genética , Proteínas Nucleares/genética , Proteínas Tirosina Fosfatasas/genética , Mucosa Respiratoria/embriología , Animales , Vasos Sanguíneos/enzimología , Ciclo Celular , Diferenciación Celular , Eliminación de Gen , Genes Letales , Proteínas Hedgehog/metabolismo , Pulmón/irrigación sanguínea , Mesodermo/enzimología , Ratones , Ratones Noqueados , Mucosa Respiratoria/citología , Mucosa Respiratoria/enzimología , Células Madre/citología , Células Madre/fisiologíaRESUMEN
A fundamental step in embryonic development is cell differentiation whereby highly specialised cell types are developed from a single undifferentiated, fertilised egg. One of the earliest lineages to form in the mammalian conceptus is the trophoblast, which contributes exclusively to the extraembryonic structures that form the placenta. Trophoblast giant cells (TGCs) in the rodent placenta form the outermost layer of the extraembryonic compartment, establish direct contact with maternal cells, and produce a number of pregnancy-specific cytokine hormones. Giant cells differentiate from proliferative trophoblasts as they exit the cell cycle and enter a genome-amplifying endocycle. Normal differentiation of secondary TGCs is a critical step toward the formation of the placenta and normal embryonic development. Trophoblast development is also of particular interest to the developmental biologist and immunobiologist, as these cells constitute the immediate cellular boundary between the embryonic and maternal tissues. Abnormalities in the development of secondary TGCs results in severe malfunction of the placenta. Herein we review new information that has been accumulated recently regarding the molecular and cellular regulation of trophoblast and placenta development. In particular, we discuss the molecular aspects of murine TGC differentiation. We also focus on the role of growth and transcription factors in TGC development.
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Regulación del Desarrollo de la Expresión Génica , Placenta/metabolismo , Trofoblastos/fisiología , Actinas/metabolismo , Animales , Ciclo Celular , Diferenciación Celular , Linaje de la Célula , Citoesqueleto/metabolismo , Biología Evolutiva/métodos , Femenino , Ratones , Embarazo , Transducción de Señal , Factores de TranscripciónRESUMEN
The differentiation of murine trophoblast giant cells (TGCs) is well characterised at the molecular level and, to some extent, the cellular level. Currently, there is a rudimentary understanding about factors regulating the cellular differentiation of secondary TGCs. Using day 8.5 p.c.-ectoplacental cone (EPC) explant in serum-free culture, we have found parathyroid hormone-related protein (PTHrP) to regulate cellular changes during TGC differentiation. PTHrP greatly stimulated the formation and organisation of actin stress fibres and actin expression in trophoblast outgrowth. This coincided with changing cell shape into a flattened/fibroblastic morphology, suppression of E-cadherin expression, and increased cell spreading in culture. PTHrP also increased the nuclear staining of beta-catenin and, similar to activator protein-2gamma (AP-2gamma), showed microtubule-dependent nuclear localisation in vitro. These cellular and behavioural changes correlated with changes in the expression of RhoGTPases and in both expression and phosphorylation of Eph/Ephrin kinases. The effects of PTHrP on trophoblast cellular differentiation were abolished after blocking its action. In conclusion, PTHrP provides an excellent example of the extrinsic factors that, through their network of activities, plays an important role in cellular differentiation of secondary TGCs.
Asunto(s)
Cadherinas/metabolismo , Citoesqueleto/metabolismo , Efrinas/metabolismo , Proteína Relacionada con la Hormona Paratiroidea/fisiología , Trofoblastos/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Actinas/metabolismo , Animales , Diferenciación Celular/fisiología , Forma de la Célula , Células Cultivadas , Femenino , Regulación del Desarrollo de la Expresión Génica , Células Gigantes/citología , Células Gigantes/metabolismo , Masculino , Ratones , Fosforilación , Placenta/citología , Placenta/metabolismo , Embarazo , Receptor EphB2/metabolismo , Factor de Transcripción AP-2/metabolismo , Trofoblastos/citología , beta Catenina/metabolismoRESUMEN
The murine trophoblast cell lineage represents an intriguing experimental cell model as it is composed of four trophoblast stem (TS)-derived cell types: trophoblast giant cells (TGCs), spongiotrophoblast, syncytotrophoblast, and glycogen trophoblast cells. To investigate the role of parathyroid hormone-related protein (PTHrP) in TGC differentiation, we analyzed the effect of exogenous PTHrP on secondary TGCs of day 8.5 p.c. ectoplacental cone explant culture. Secondary TGCs expressed PTHrP and PTHR1 receptor in vivo and in vitro. TGCs treated with PTHrP had reduced proliferation and decreased apoptosis starting from day 2 in culture, and enhanced properties of giant cell differentiation: increased DNA synthesis, number of cells with giant nuclei and expression of placental lactogen-II (PL-II). The induction of TGC formation by PTHrP correlated with downregulation of cyclin B1 and mSNA expression, but upregulation of cyclin D1, thus allowing mitotic-endocycle transition. Moreover, PTHrP treatment influenced TGC differentiation by inducing the expression of transcription factors known to stimulate giant cell formation: Stra13 and AP-2gamma, and inhibiting the formation of other trophoblast cell types by suppressing trophoblast progenitors and spongiotrophoblast-promoting factors, Eomes, Mash-2, and mSNA. Taken together with the spatial and temporal patterns of TGC formation and PTHrP synthesis in vivo, these findings indicate an important role for PTHrP in the differentiation of secondary TGCs during placentation.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Células Gigantes/citología , Proteínas de Homeodominio/metabolismo , Proteína Relacionada con la Hormona Paratiroidea/fisiología , Factores de Transcripción/metabolismo , Trofoblastos/citología , Regulación hacia Arriba , Animales , Apoptosis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Biomarcadores/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciación Celular , Núcleo Celular/metabolismo , Proliferación Celular , Replicación del ADN , Proteínas de Unión al ADN/análisis , Femenino , Regulación del Desarrollo de la Expresión Génica , Células Gigantes/efectos de los fármacos , Células Gigantes/metabolismo , Proteínas de Homeodominio/análisis , Masculino , Ratones , Proteína Relacionada con la Hormona Paratiroidea/farmacología , Lactógeno Placentario/genética , Lactógeno Placentario/metabolismo , Receptor de Hormona Paratiroídea Tipo 1/análisis , Receptor de Hormona Paratiroídea Tipo 1/metabolismo , Factor de Transcripción AP-2 , Factores de Transcripción/análisis , Trofoblastos/efectos de los fármacos , Trofoblastos/metabolismoRESUMEN
Primary aortic angiosarcomas are extremely rare. Clinically and radiographically, they mimic atherosclerosis and atheroembolic disease. For a definitive diagnosis, histologic evaluation of the tumor or of peripheral emboli is required. The imaging findings are frequently nonspecific and in most published cases did not allow a definitive preoperative diagnosis. This is the first report of the computed tomographic angiographic findings of a primary intimal abdominal aortic sarcoma and a review of previously described imaging findings in these tumors.