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1.
Proc Natl Acad Sci U S A ; 121(28): e2317711121, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38968101

RESUMO

Adult neural stem cells (NSCs) reside in the dentate gyrus of the hippocampus, and their capacity to generate neurons and glia plays a role in learning and memory. In addition, neurodegenerative diseases are known to be caused by a loss of neurons and glial cells, resulting in a need to better understand stem cell fate commitment processes. We previously showed that NSC fate commitment toward a neuronal or glial lineage is strongly influenced by extracellular matrix stiffness, a property of elastic materials. However, tissues in vivo are not purely elastic and have varying degrees of viscous character. Relatively little is known about how the viscoelastic properties of the substrate impact NSC fate commitment. Here, we introduce a polyacrylamide-based cell culture platform that incorporates mismatched DNA oligonucleotide-based cross-links as well as covalent cross-links. This platform allows for tunable viscous stress relaxation properties via variation in the number of mismatched base pairs. We find that NSCs exhibit increased astrocytic differentiation as the degree of stress relaxation is increased. Furthermore, culturing NSCs on increasingly stress-relaxing substrates impacts cytoskeletal dynamics by decreasing intracellular actin flow rates and stimulating cyclic activation of the mechanosensitive protein RhoA. Additionally, inhibition of motor-clutch model components such as myosin II and focal adhesion kinase partially or completely reverts cells to lineage distributions observed on elastic substrates. Collectively, our results introduce a unique system for controlling matrix stress relaxation properties and offer insight into how NSCs integrate viscoelastic cues to direct fate commitment.


Assuntos
Diferenciação Celular , Células-Tronco Neurais , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/fisiologia , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Astrócitos/fisiologia , Camundongos , Resinas Acrílicas/química , Proteína rhoA de Ligação ao GTP/metabolismo , Células Cultivadas , Neurônios/metabolismo , Neurônios/fisiologia , Neurônios/citologia , Matriz Extracelular/metabolismo , Estresse Mecânico
2.
Sci Adv ; 10(27): eado9120, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38959311

RESUMO

A bioinspired hydrogel composed of hyaluronic acid-graft-dopamine (HADA) and a designer peptide HGF-(RADA)4-DGDRGDS (HRR) was presented to enhance tissue integration following spinal cord injury (SCI). The HADA/HRR hydrogel manipulated the infiltration of PDGFRß+ cells in a parallel pattern, transforming dense scars into an aligned fibrous substrate that guided axonal regrowth. Further incorporation of NT3 and curcumin promoted axonal regrowth and survival of interneurons at lesion borders, which served as relays for establishing heterogeneous axon connections in a target-specific manner. Notable improvements in motor, sensory, and bladder functions resulted in rats with complete spinal cord transection. The HADA/HRR + NT3/Cur hydrogel promoted V2a neuron accumulation in ventral spinal cord, facilitating the recovery of locomotor function. Meanwhile, the establishment of heterogeneous neural connections across the hemisected lesion of canines was documented in a target-specific manner via neuronal relays, significantly improving motor functions. Therefore, biomaterials can inspire beneficial biological activities for SCI repair.


Assuntos
Matriz Extracelular , Hidrogéis , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Animais , Hidrogéis/química , Ratos , Matriz Extracelular/metabolismo , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Cães , Axônios/metabolismo , Axônios/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Ácido Hialurônico/química , Ácido Hialurônico/metabolismo , Recuperação de Função Fisiológica/efeitos dos fármacos , Dopamina/metabolismo , Feminino , Modelos Animais de Doenças , Ratos Sprague-Dawley , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Medula Espinal/metabolismo
3.
Adv Protein Chem Struct Biol ; 141: 361-380, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38960480

RESUMO

Multicellular organisms consist of cells and extracellular matrix (ECM). ECM creates a cellular microenvironment, and cells locally degrade the ECM according to their cellular activity. A major group of enzymes that modify ECM belongs to matrix metalloproteinases (MMPs) and play major roles in various pathophysiological events. ECM degradation by MMPs does not occur in all cellular surroundings but only where it is necessary, and cells achieve this by directionally secreting these proteolytic enzymes. Recent studies have indicated that such enzyme secretion is achieved by targeted vesicle transport along the microtubules, and several kinesin superfamily proteins (KIFs) have been identified as responsible motor proteins involved in the processes. This chapter discusses recent findings of the vesicle transport of MMPs and their roles.


Assuntos
Metaloproteinases da Matriz , Metaloproteinases da Matriz/metabolismo , Humanos , Animais , Cinesinas/metabolismo , Cinesinas/química , Matriz Extracelular/metabolismo , Transporte Biológico , Microtúbulos/metabolismo
4.
PLoS One ; 19(7): e0306248, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38950058

RESUMO

Diabetic foot ulcers (DFUs) pose a significant challenge in diabetes care. Yet, a comprehensive understanding of the underlying biological disparities between healing and non-healing DFUs remains elusive. We conducted bioinformatics analysis of publicly available transcriptome sequencing data in an attempt to elucidate these differences. Our analysis encompassed differential analysis to unveil shifts in cell composition and gene expression profiles between non-healing and healing DFUs. Cell communication alterations were explored employing the Cellchat R package. Pseudotime analysis and cytoTRACE allowed us to dissect the heterogeneity within fibroblast subpopulations. Our findings unveiled disruptions in various cell types, localized low-grade inflammation, compromised systemic antigen processing and presentation, and extensive extracellular matrix signaling disarray in non-healing DFU patients. Some of these anomalies partially reverted in healing DFUs, particularly within the abnormal ECM-receptor signaling pathway. Furthermore, we distinguished distinct fibroblast subpopulations in non-healing and healing DFUs, each with unique biological functions. Healing-associated fibroblasts exhibited heightened extracellular matrix (ECM) remodeling and a robust wound healing response, while non-healing-associated fibroblasts showed signs of cellular senescence and complement activation, among other characteristics. This analysis offers profound insights into the wound healing microenvironment, identifies pivotal cell types for DFU healing promotion, and reveals potential therapeutic targets for DFU management.


Assuntos
Pé Diabético , Fibroblastos , Análise de Célula Única , Transcriptoma , Cicatrização , Pé Diabético/genética , Pé Diabético/patologia , Pé Diabético/metabolismo , Humanos , Cicatrização/genética , Análise de Célula Única/métodos , Fibroblastos/metabolismo , Fibroblastos/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/genética , Perfilação da Expressão Gênica , Transdução de Sinais/genética
5.
Chin J Dent Res ; 27(2): 121-131, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38953477

RESUMO

As the biological mechanisms of orthodontic tooth movement have been explored further, scholars have gradually focused on the remodelling mechanism of the extracellular matrix (ECM) in the periodontal ligament (PDL). The ECM of the PDL consists of various types of collagens and other glycoproteins. The specific process and mechanism of ECM remodelling during orthodontic tooth movement remains unclear. Collagen I and III, which constitute major components of the PDL, are upregulated under orthodontic force. The changes in the contents of ECM proteins also depend on the expression of ECM-related enzymes, which organise new collagen fibre networks to adapt to changes in tooth position. The matrix metalloproteinase family is the main enzyme that participates in collagen hydrolysis and renewal and changes its expression under orthodontic force. Moreover, ECM adhesion molecules, such as integrins, are also regulated by orthodontic force and participate in the dynamic reaction of cell adhesion and separation with the ECM. This article reviews the changes in ECM components, related enzymes and adhesion molecules in the PDL under orthodontic force to lay the foundation for the exploration of the regulatory mechanism of ECM remodelling during orthodontic tooth movement.


Assuntos
Matriz Extracelular , Ligamento Periodontal , Técnicas de Movimentação Dentária , Matriz Extracelular/metabolismo , Humanos , Técnicas de Movimentação Dentária/métodos , Ligamento Periodontal/citologia , Periodonto/metabolismo , Metaloproteinases da Matriz/metabolismo , Integrinas/metabolismo , Colágeno/metabolismo
6.
Proc Natl Acad Sci U S A ; 121(28): e2404210121, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38954541

RESUMO

Mesenchymal stem cells (MSCs) are essential in regenerative medicine. However, conventional expansion and harvesting methods often fail to maintain the essential extracellular matrix (ECM) components, which are crucial for their functionality and efficacy in therapeutic applications. Here, we introduce a bone marrow-inspired macroporous hydrogel designed for the large-scale production of MSC-ECM spheroids. Through a soft-templating approach leveraging liquid-liquid phase separation, we engineer macroporous hydrogels with customizable features, including pore size, stiffness, bioactive ligand distribution, and enzyme-responsive degradability. These tailored environments are conducive to optimal MSC proliferation and ease of harvesting. We find that soft hydrogels enhance mechanotransduction in MSCs, establishing a standard for hydrogel-based 3D cell culture. Within these hydrogels, MSCs exist as both cohesive spheroids, preserving their innate vitality, and as migrating entities that actively secrete functional ECM proteins. Additionally, we also introduce a gentle, enzymatic harvesting method that breaks down the hydrogels, allowing MSCs and secreted ECM to naturally form MSC-ECM spheroids. These spheroids display heightened stemness and differentiation capacity, mirroring the benefits of a native ECM milieu. Our research underscores the significance of sophisticated materials design in nurturing distinct MSC subpopulations, facilitating the generation of MSC-ECM spheroids with enhanced therapeutic potential.


Assuntos
Matriz Extracelular , Hidrogéis , Células-Tronco Mesenquimais , Esferoides Celulares , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Hidrogéis/química , Matriz Extracelular/metabolismo , Esferoides Celulares/citologia , Esferoides Celulares/metabolismo , Humanos , Diferenciação Celular , Técnicas de Cultura de Células/métodos , Proliferação de Células , Porosidade , Mecanotransdução Celular/fisiologia , Células Cultivadas
7.
Invest Ophthalmol Vis Sci ; 65(8): 1, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38949632

RESUMO

Purpose: Glucocorticoid-induced glaucoma (GIG) is a prevalent complication associated with glucocorticoids (GCs), resulting in irreversible blindness. GIG is characterized by the abnormal deposition of extracellular matrix (ECM) in the trabecular meshwork (TM), elevation of intraocular pressure (IOP), and loss of retinal ganglion cells (RGCs). The objective of this study is to investigate the effects of nicotinamide riboside (NR) on TM in GIG. Methods: Primary human TM cells (pHTMs) and C57BL/6J mice responsive to GCs were utilized to establish in vitro and in vivo GIG models, respectively. The study assessed the expression of ECM-related proteins in TM and the functions of pHTMs to reflect the effects of NR. Mitochondrial morphology and function were also examined in the GIG cell model. GIG progression was monitored through IOP, RGCs, and mitochondrial morphology. Intracellular nicotinamide adenine dinucleotide (NAD+) levels of pHTMs were enzymatically assayed. Results: NR significantly prevented the expression of ECM-related proteins and alleviated dysfunction in pHTMs after dexamethasone treatment. Importantly, NR protected damaged ATP synthesis, preventing overexpression of mitochondrial reactive oxygen species (ROS), and also protect against decreased mitochondrial membrane potential induced by GCs in vitro. In the GIG mouse model, NR partially prevented the elevation of IOP and the loss of RGCs. Furthermore, NR effectively suppressed the excessive expression of ECM-associated proteins and mitigated mitochondrial damage in vivo. Conclusions: Based on the results, NR effectively enhances intracellular levels of NAD+, thereby mitigating abnormal ECM deposition and TM dysfunction in GIG by attenuating mitochondrial damage induced by GCs. Thus, NR has promising potential as a therapeutic candidate for GIG treatment.


Assuntos
Modelos Animais de Doenças , Matriz Extracelular , Glaucoma , Glucocorticoides , Pressão Intraocular , Camundongos Endogâmicos C57BL , Mitocôndrias , Niacinamida , Compostos de Piridínio , Malha Trabecular , Animais , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Piridínio/farmacologia , Glucocorticoides/toxicidade , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Camundongos , Glaucoma/metabolismo , Glaucoma/tratamento farmacológico , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacos , Pressão Intraocular/efeitos dos fármacos , Humanos , Malha Trabecular/metabolismo , Malha Trabecular/efeitos dos fármacos , Malha Trabecular/patologia , Células Cultivadas , Células Ganglionares da Retina/efeitos dos fármacos , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Espécies Reativas de Oxigênio/metabolismo , Dexametasona/farmacologia , Masculino
8.
Sci Rep ; 14(1): 15304, 2024 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-38961188

RESUMO

Inflammation, corticosteroids, and loading all affect tendon healing, with an interaction between them. However, underlying mechanisms behind the effect of corticosteroids and the interaction with loading remain unclear. The aim of this study was to investigate the role of dexamethasone during tendon healing, including specific effects on tendon cells. Rats (n = 36) were randomized to heavy loading or mild loading, the Achilles tendon was transected, and animals were treated with dexamethasone or saline. Gene and protein analyses of the healing tendon were performed for extracellular matrix-, inflammation-, and tendon cell markers. We further tested specific effects of dexamethasone on tendon cells in vitro. Dexamethasone increased mRNA levels of S100A4 and decreased levels of ACTA2/α-SMA, irrespective of load level. Heavy loading + dexamethasone reduced mRNA levels of FN1 and TenC (p < 0.05), while resolution-related genes were unaltered (p > 0.05). In contrast, mild loading + dexamethasone increased mRNA levels of resolution-related genes ANXA1, MRC1, PDPN, and PTGES (p < 0.03). Altered protein levels were confirmed in tendons with mild loading. Dexamethasone treatment in vitro prevented tendon construct formation, increased mRNA levels of S100A4 and decreased levels of SCX and collagens. Dexamethasone during tendon healing appears to act through immunomodulation by promoting resolution, but also through an effect on tendon cells.


Assuntos
Tendão do Calcâneo , Dexametasona , Traumatismos dos Tendões , Cicatrização , Dexametasona/farmacologia , Animais , Ratos , Cicatrização/efeitos dos fármacos , Traumatismos dos Tendões/tratamento farmacológico , Traumatismos dos Tendões/metabolismo , Tendão do Calcâneo/efeitos dos fármacos , Tendão do Calcâneo/metabolismo , Tendão do Calcâneo/lesões , Tendão do Calcâneo/patologia , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Proteína A4 de Ligação a Cálcio da Família S100/genética , Masculino , Anexina A1/metabolismo , Anexina A1/genética , Actinas/metabolismo , Actinas/genética , Colágeno/metabolismo , Ratos Sprague-Dawley , Tendões/efeitos dos fármacos , Tendões/metabolismo , Matriz Extracelular/metabolismo , Matriz Extracelular/efeitos dos fármacos , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos
9.
Sci Rep ; 14(1): 15022, 2024 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-38951570

RESUMO

Cartilage tissue engineering aims to develop functional substitutes for treating cartilage defects and osteoarthritis. Traditional two-dimensional (2D) cell culture systems lack the complexity of native cartilage, leading to the development of 3D regenerative cartilage models. In this study, we developed a 3D model using Gelatin Methacryloyl (GelMA)-based hydrogels seeded with Y201 cells, a bone marrow mesenchymal stem cell line. The model investigated chondrogenic differentiation potential in response to Wnt3a stimulation within the GelMA scaffold and validated using known chondrogenic agonists. Y201 cells demonstrated suitability for the model, with increased proteoglycan content and upregulated chondrogenic marker expression under chondrogenic conditions. Wnt3a enhanced cell proliferation, indicating activation of the Wnt/ß-catenin pathway, which plays a role in cartilage development. GelMA hydrogels provided an optimal scaffold, supporting cell viability and proliferation. The 3D model exhibited consistent responses to chondrogenic agonists, with TGF-ß3 enhancing cartilage-specific extracellular matrix (ECM) production and chondrogenic differentiation. The combination of Wnt3a and TGF-ß3 showed synergistic effects, promoting chondrogenic differentiation and ECM production. This study presents a 3D regenerative cartilage model with potential for investigating cartilage biology, disease mechanisms, and drug screening. The model provides insights into complex cartilage regeneration mechanisms and offers a platform for developing therapeutic approaches for cartilage repair and osteoarthritis treatment.


Assuntos
Diferenciação Celular , Proliferação de Células , Condrogênese , Hidrogéis , Células-Tronco Mesenquimais , Engenharia Tecidual , Proteína Wnt3A , Proteína Wnt3A/metabolismo , Condrogênese/efeitos dos fármacos , Engenharia Tecidual/métodos , Proliferação de Células/efeitos dos fármacos , Hidrogéis/química , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Humanos , Cartilagem/metabolismo , Gelatina/química , Alicerces Teciduais/química , Fator de Crescimento Transformador beta3/metabolismo , Fator de Crescimento Transformador beta3/farmacologia , Linhagem Celular , Matriz Extracelular/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/citologia , Animais
10.
Front Immunol ; 15: 1379570, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38957465

RESUMO

There is a reciprocal relationship between extracellular matrix (ECM) remodelling and inflammation that could be operating in the progression of severe COVID-19. To explore the immune-driven ECM remodelling in COVID-19, we in this explorative study analysed these interactions in hospitalised COVID-19 patients. RNA sequencing and flow analysis were performed on peripheral blood mononuclear cells. Inflammatory mediators in plasma were measured by ELISA and MSD, and clinical information from hospitalised COVID-19 patients (N=15) at admission was included in the analysis. Further, we reanalysed two publicly available datasets: (1) lung tissue RNA-sequencing dataset (N=5) and (2) proteomics dataset from PBCM. ECM remodelling pathways were enriched in PBMC from COVID-19 patients compared to healthy controls. Patients treated at the intensive care unit (ICU) expressed distinct ECM remodelling gene profiles compared to patients in the hospital ward. Several markers were strongly correlated to immune cell subsets, and the dysregulation in the ICU patients was positively associated with plasma levels of inflammatory cytokines and negatively associated with B-cell activating factors. Finally, our analysis of publicly accessible datasets revealed (i) an augmented ECM remodelling signature in inflamed lung tissue compared to non-inflamed tissue and (ii) proteomics analysis of PBMC from severe COVID-19 patients demonstrated an up-regulation in an ECM remodelling pathway. Our results may suggest the presence of an interaction between ECM remodelling, inflammation, and immune cells, potentially initiating or perpetuating pulmonary pathology in severe COVID-19.


Assuntos
COVID-19 , Matriz Extracelular , Leucócitos Mononucleares , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/sangue , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Matriz Extracelular/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , SARS-CoV-2/fisiologia , SARS-CoV-2/imunologia , Idoso , Citocinas/sangue , Proteômica/métodos , Pulmão/imunologia , Pulmão/patologia , Adulto
11.
Hepatol Commun ; 8(7)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38967589

RESUMO

BACKGROUND: Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events. METHODS: Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test. RESULTS: Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001). CONCLUSIONS: Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC.


Assuntos
Anticorpos Monoclonais Humanizados , Biomarcadores , Colangite Esclerosante , Progressão da Doença , Matriz Extracelular , Cirrose Hepática , Humanos , Colangite Esclerosante/tratamento farmacológico , Colangite Esclerosante/sangue , Colangite Esclerosante/patologia , Masculino , Feminino , Biomarcadores/sangue , Prognóstico , Adulto , Cirrose Hepática/sangue , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/etiologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Pessoa de Meia-Idade , Matriz Extracelular/patologia , Índice de Gravidade de Doença , Ácido Hialurônico/sangue , Fígado/patologia
12.
Sci Rep ; 14(1): 15556, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38969656

RESUMO

Previously, we reported successful cellular expansion of a murine colorectal carcinoma cell line (CT-26) using a three-dimensional (3D) engineered extracellular matrix (EECM) fibrillar scaffold structure. CCL-247 were grown over a limited time period of 8 days on 3D EECM or tissue culture polystyrene (TCPS). Cells were then assayed for growth, electroporation efficiency and Vigil manufacturing release criteria. Using EECM scaffolds, we report an expansion of CCL-247 (HCT116), a colorectal carcinoma cell line, from a starting concentration of 2.45 × 105 cells to 1.9 × 106 cells per scaffold. Following expansion, 3D EECM-derived cells were assessed based on clinical release criteria of the Vigil manufacturing process utilized for Phase IIb trial operation with the FDA. 3D EECM-derived cells passed all Vigil manufacturing release criteria including cytokine expression. Here, we demonstrate successful Vigil product manufacture achieving the specifications necessary for the clinical trial product release of Vigil treatment. Our results confirm that 3D EECM can be utilized for the expansion of human cancer cell CCL-247, justifying further clinical development involving human tissue sample manufacturing including core needle biopsy and minimal ascites samples.


Assuntos
Matriz Extracelular , Imunoterapia , Alicerces Teciduais , Humanos , Alicerces Teciduais/química , Imunoterapia/métodos , Engenharia Tecidual/métodos , Células HCT116 , Neoplasias Colorretais/patologia , Animais , Camundongos , Proliferação de Células , Linhagem Celular Tumoral , Técnicas de Cultura de Células em Três Dimensões/métodos
13.
Cell Mol Neurobiol ; 44(1): 54, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38969910

RESUMO

The extracellular matrix (ECM) is a dynamic set of molecules produced by the cellular component of normal and pathological tissues of the embryo and adult. ECM acts as critical regulator in various biological processes such as differentiation, cell proliferation, angiogenesis, and immune control. The most frequent primary brain tumors are gliomas and by far the majority are adult astrocytic tumors (AATs). The prognosis for patients with these neoplasms is poor and the treatments modestly improves survival. In the literature, there is a fair number of studies concerning the composition of the ECM in AATs, while the number of studies relating the composition of the ECM with the immune regulation is smaller. Circulating ECM proteins have emerged as a promising biomarker that reflect the general immune landscape of tumor microenvironment and may represent a useful tool in assessing disease activity. Given the importance it can have for therapeutic and prognostic purposes, the aim of our study is to summarize the biological properties of ECM components and their effects on the tumor microenvironment and to provide an overview of the interactions between major ECM proteins and immune cells in AATs. As the field of immunotherapy in glioma is quickly expanding, we retain that current data together with future studies on ECM organization and functions in glioma will provide important insights into the tuning of immunotherapeutic approaches.


Assuntos
Astrocitoma , Matriz Extracelular , Microambiente Tumoral , Humanos , Matriz Extracelular/metabolismo , Microambiente Tumoral/imunologia , Astrocitoma/patologia , Astrocitoma/metabolismo , Astrocitoma/imunologia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/metabolismo , Adulto , Animais , Proteínas da Matriz Extracelular/metabolismo
14.
J Ovarian Res ; 17(1): 139, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38970048

RESUMO

Ovarian fibrosis, characterized by the excessive proliferation of ovarian fibroblasts and the accumulation of extracellular matrix (ECM), serves as one of the primary causes of ovarian dysfunction. Despite the critical role of ovarian fibrosis in maintaining the normal physiological function of the mammalian ovaries, research on this condition has been greatly underestimated, which leads to a lack of clinical treatment options for ovarian dysfunction caused by fibrosis. This review synthesizes recent research on the molecular mechanisms of ovarian fibrosis, encompassing TGF-ß, extracellular matrix, inflammation, and other profibrotic factors contributing to abnormal ovarian fibrosis. Additionally, we summarize current treatment approaches for ovarian dysfunction targeting ovarian fibrosis, including antifibrotic drugs, stem cell transplantation, and exosomal therapies. The purpose of this review is to summarize the research progress on ovarian fibrosis and to propose potential therapeutic strategies targeting ovarian fibrosis for the treatment of ovarian dysfunction.


Assuntos
Fibrose , Ovário , Humanos , Feminino , Ovário/patologia , Ovário/metabolismo , Animais , Matriz Extracelular/metabolismo , Doenças Ovarianas/metabolismo , Doenças Ovarianas/patologia , Doenças Ovarianas/terapia , Terapia de Alvo Molecular , Fator de Crescimento Transformador beta/metabolismo
15.
Sci Signal ; 17(844): eado5279, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38980923

RESUMO

In this issue of Science Signaling, Jackson et al. present a new antibody strategy to-quite literally-strap transforming growth factor-ß1 (TGF-ß1) to latent complexes in the extracellular matrix. The antibody has no effect on latent TGF-ß1 presented on the surface of immune cells and thus allows targeting of the detrimental effects of TGF-ß1 in fibrosis without affecting its beneficial immune-suppressing activities.


Assuntos
Matriz Extracelular , Fator de Crescimento Transformador beta1 , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/imunologia , Humanos , Matriz Extracelular/metabolismo , Matriz Extracelular/imunologia , Animais , Fibrose , Anticorpos/imunologia , Anticorpos/metabolismo , Camundongos
16.
Sci Signal ; 17(844): eadn6052, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38980922

RESUMO

Inhibitors of the transforming growth factor-ß (TGF-ß) pathway are potentially promising antifibrotic therapies, but nonselective simultaneous inhibition of all three TGF-ß homologs has safety liabilities. TGF-ß1 is noncovalently bound to a latency-associated peptide that is, in turn, covalently bound to different presenting molecules within large latent complexes. The latent TGF-ß-binding proteins (LTBPs) present TGF-ß1 in the extracellular matrix, and TGF-ß1 is presented on immune cells by two transmembrane proteins, glycoprotein A repetitions predominant (GARP) and leucine-rich repeat protein 33 (LRRC33). Here, we describe LTBP-49247, an antibody that selectively bound to and inhibited the activation of TGF-ß1 presented by LTBPs but did not bind to TGF-ß1 presented by GARP or LRRC33. Structural studies demonstrated that LTBP-49247 recognized an epitope on LTBP-presented TGF-ß1 that is not accessible on GARP- or LRRC33-presented TGF-ß1, explaining the antibody's selectivity for LTBP-complexed TGF-ß1. In two rodent models of kidney fibrosis of different etiologies, LTBP-49247 attenuated fibrotic progression, indicating the central role of LTBP-presented TGF-ß1 in renal fibrosis. In mice, LTBP-49247 did not have the toxic effects associated with less selective TGF-ß inhibitors. These results establish the feasibility of selectively targeting LTBP-bound TGF-ß1 as an approach for treating fibrosis.


Assuntos
Matriz Extracelular , Fibrose , Proteínas de Ligação a TGF-beta Latente , Fator de Crescimento Transformador beta1 , Fator de Crescimento Transformador beta1/metabolismo , Animais , Humanos , Proteínas de Ligação a TGF-beta Latente/metabolismo , Proteínas de Ligação a TGF-beta Latente/antagonistas & inibidores , Matriz Extracelular/metabolismo , Camundongos , Masculino , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/tratamento farmacológico , Progressão da Doença , Rim/patologia , Rim/metabolismo , Rim/efeitos dos fármacos , Camundongos Endogâmicos C57BL
17.
Development ; 151(13)2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38984541

RESUMO

The cardiac extracellular matrix (cECM) is fundamental for organ morphogenesis and maturation, during which time it undergoes remodeling, yet little is known about whether mechanical forces generated by the heartbeat regulate this remodeling process. Using zebrafish as a model and focusing on stages when cardiac valves and trabeculae form, we found that altering cardiac contraction impairs cECM remodeling. Longitudinal volumetric quantifications in wild-type animals revealed region-specific dynamics: cECM volume decreases in the atrium but not in the ventricle or atrioventricular canal. Reducing cardiac contraction resulted in opposite effects on the ventricular and atrial ECM, whereas increasing the heart rate affected the ventricular ECM but had no effect on the atrial ECM, together indicating that mechanical forces regulate the cECM in a chamber-specific manner. Among the ECM remodelers highly expressed during cardiac morphogenesis, we found one that was upregulated in non-contractile hearts, namely tissue inhibitor of matrix metalloproteinase 2 (timp2). Loss- and gain-of-function analyses of timp2 revealed its crucial role in cECM remodeling. Altogether, our results indicate that mechanical forces control cECM remodeling in part through timp2 downregulation.


Assuntos
Matriz Extracelular , Coração , Inibidor Tecidual de Metaloproteinase-2 , Peixe-Zebra , Animais , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Matriz Extracelular/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Coração/embriologia , Proteínas de Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Morfogênese , Átrios do Coração/embriologia , Átrios do Coração/metabolismo , Fenômenos Biomecânicos , Regulação da Expressão Gênica no Desenvolvimento , Ventrículos do Coração/metabolismo , Ventrículos do Coração/embriologia
18.
Physiology (Bethesda) ; 39(5): 0, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38984789

RESUMO

Alterations in vascular extracellular matrix (ECM) components, interactions, and mechanical properties influence both the formation and stability of atherosclerotic plaques. This review discusses the contribution of the ECM microenvironment in vascular homeostasis and remodeling in atherosclerosis, highlighting Cartilage oligomeric matrix protein (COMP) and its degrading enzyme ADAMTS7 as examples, and proposes potential avenues for future research aimed at identifying novel therapeutic targets for atherosclerosis based on the ECM microenvironment.


Assuntos
Aterosclerose , Matriz Extracelular , Homeostase , Humanos , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Aterosclerose/patologia , Animais , Matriz Extracelular/metabolismo , Homeostase/fisiologia , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Remodelação Vascular/fisiologia
19.
Med Sci (Paris) ; 40(6-7): 515-524, 2024.
Artigo em Francês | MEDLINE | ID: mdl-38986096

RESUMO

Invadosome is an umbrella term used to describe a family of cellular structures including podosomes and invadopodia. They serve as contact zones between the cell plasma membrane and extracellular matrix, contributing to matrix remodeling by locally enriched proteolytic enzymes. Invadosomes, which are actin-dependent, are implicated in cellular processes promoting adhesion, migration, and invasion. Invadosomes, which exist in various cell types, play crucial roles in physiological phenomena such as vascularization and bone resorption. Invadosomes are also implicated in pathological processes such as matrix tissue remodeling during metastatic tumor cell invasion. This review summarizes basic information and recent advances about mechanisms underlying podosome and invadopodia formation, their organization and function.


Title: Invadosomes - Entre mobilité et invasion, naviguer dans la dualité des fonctions cellulaires. Abstract: Le terme « invadosome ¼ désigne une famille de structures cellulaires, comprenant les podosomes et les invadopodes, qui constituent des zones de contact entre la membrane plasmique des cellules et la matrice extracellulaire. Ces structures contribuent au remodelage de la matrice grâce à un enrichissement local en enzymes protéolytiques qui dégradent ses constituants fibrillaires. Les invadosomes, présents dans des types cellulaires variés, contribuent à des processus physiologiques, tels que la vascularisation, ou pathologiques, comme l'invasion des tissus par les cellules métastatiques.


Assuntos
Movimento Celular , Matriz Extracelular , Invasividade Neoplásica , Neoplasias , Podossomos , Humanos , Podossomos/fisiologia , Podossomos/patologia , Movimento Celular/fisiologia , Animais , Neoplasias/patologia , Matriz Extracelular/fisiologia , Matriz Extracelular/patologia
20.
Nat Commun ; 15(1): 5795, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38987250

RESUMO

Animals protect themself from microbial attacks by robust skins or a cuticle as in Caenorhabditis elegans. Nematode-trapping fungi, like Arthrobotrys flagrans, overcome the cuticle barrier and colonize the nematode body. While lytic enzymes are important for infection, small-secreted proteins (SSPs) without enzymatic activity, emerge as crucial virulence factors. Here, we characterized NipA (nematode induced protein) which A. flagrans secretes at the penetration site. In the absence of NipA, A. flagrans required more time to penetrate C. elegans. Heterologous expression of the fungal protein in the epidermis of C. elegans led to blister formation. NipA contains 13 cysteines, 12 of which are likely to form disulfide bridges, and the remaining cysteine was crucial for blister formation. We hypothesize that NipA interferes with cuticle integrity to facilitate fungal entry. Genome-wide expression analyses of C. elegans expressing NipA revealed mis-regulation of genes associated with extracellular matrix (ECM) maintenance and innate immunity.


Assuntos
Ascomicetos , Caenorhabditis elegans , Cisteína , Proteínas Fúngicas , Fatores de Virulência , Animais , Caenorhabditis elegans/microbiologia , Fatores de Virulência/metabolismo , Fatores de Virulência/genética , Cisteína/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Ascomicetos/patogenicidade , Ascomicetos/genética , Ascomicetos/metabolismo , Imunidade Inata , Matriz Extracelular/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Epiderme/metabolismo , Epiderme/microbiologia
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