• MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell genetics   MeSH
• DNA-Directed DNA Polymerase genetics   metabolism   MeSH
• DNA Primase genetics   metabolism   MeSH
• Extracellular Matrix metabolism   pathology   MeSH
• Genes, p53 genetics   MeSH
• Glioblastoma metabolism   pathology   MeSH
• Pericytes metabolism   pathology   MeSH
• BRCA1 Protein genetics   metabolism   MeSH
• Publication type
• Overall MeSH

Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibrostenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate the mechanisms underlying fibrostenosis in CD, we analyzed the transcriptome of cells isolated from the transmural ileum of patients with CD, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from patients without CD. Our computational analysis revealed that profibrotic signals from a subset of monocyte-derived cells expressing CD150 induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) deposition. Genetic and pharmacological inhibition of TWIST1 prevents fibroblast activation, reducing ECM production and collagen deposition. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibrostenosis in CD.

• MeSH
• Crohn Disease * metabolism   pathology   immunology   MeSH
• Adult MeSH
• Endopeptidases metabolism   genetics   MeSH
• Extracellular Matrix metabolism   pathology   MeSH
• Fibroblasts * metabolism   pathology   MeSH
• Fibrosis * MeSH
• Ileum pathology   metabolism   immunology   MeSH
• Nuclear Proteins metabolism   genetics   MeSH
• Humans MeSH
• Cell Communication MeSH
• Monocytes * metabolism   pathology   immunology   MeSH
• Mice MeSH
• Receptors, Cell Surface metabolism   genetics   MeSH
• Twist-Related Protein 1 * metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Recent research has identified that miR-539-3p impedes chondrogenic differentiation, yet its specific role and underlying mechanisms in childhood-onset osteoarthritis (OA) remain unclear. This study found that miR-539-3p levels were considerably lower in cartilage samples derived from childhood-onset OA patients compared to the control group. Enhancing miR-539-3p expression or suppressing RUNX2 expression notably reduced apoptosis, inflammation, and extracellular matrix (ECM) degradation in OA chondrocytes. In contrast, reducing miR-539-3p or increasing RUNX2 had the opposite effects. RUNX2 was confirmed as a direct target of miR-539-3p. Further experiments demonstrated that miR-539-3p targeting RUNX2 effectively lessened apoptosis, inflammation, and ECM degradation in OA chondrocytes, accompanied by changes in key molecular markers like reduced caspase-3 and matrix etallopeptidase 13 (MMP-13) levels, and increased B-cell lymphoma 2 (Bcl-2) and collagen type X alpha 1 chain (COL2A1). This study underscores the pivotal role of miR-539-3p in alleviating inflammation and ECM degradation in childhood-onset OA through targeting RUNX2, offering new insights for potential therapeutic strategies against this disease.

• MeSH
• Apoptosis * MeSH
• Chondrocytes * metabolism   pathology   MeSH
• Child MeSH
• Extracellular Matrix * metabolism   pathology   MeSH
• Cells, Cultured MeSH
• Humans MeSH
• MicroRNAs * metabolism   genetics   MeSH
• Adolescent MeSH
• Osteoarthritis * metabolism   pathology   genetics   MeSH
• Core Binding Factor Alpha 1 Subunit * metabolism   genetics   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Gliomagenesis induces profound changes in the composition of the extracellular matrix (ECM) of the brain. In this study, we identified a cellular population responsible for the increased deposition of collagen I and fibronectin in glioblastoma. Elevated levels of the fibrillar proteins collagen I and fibronectin were associated with the expression of fibroblast activation protein (FAP), which is predominantly found in pericyte-like cells in glioblastoma. FAP+ pericyte-like cells were present in regions rich in collagen I and fibronectin in biopsy material and produced substantially more collagen I and fibronectin in vitro compared to other cell types found in the GBM microenvironment. Using mass spectrometry, we demonstrated that 3D matrices produced by FAP+ pericyte-like cells are rich in collagen I and fibronectin and contain several basement membrane proteins. This expression pattern differed markedly from glioma cells. Finally, we have shown that ECM produced by FAP+ pericyte-like cells enhances the migration of glioma cells including glioma stem-like cells, promotes their adhesion, and activates focal adhesion kinase (FAK) signaling. Taken together, our findings establish FAP+ pericyte-like cells as crucial producers of a complex ECM rich in collagen I and fibronectin, facilitating the dissemination of glioma cells through FAK activation.

• MeSH
• Endopeptidases MeSH
• Extracellular Matrix * metabolism   pathology   MeSH
• Fibronectins * metabolism   MeSH
• Glioblastoma pathology   metabolism   MeSH
• Glioma * pathology   metabolism   MeSH
• Collagen Type I metabolism   MeSH
• Humans MeSH
• Membrane Proteins metabolism   MeSH
• Cell Line, Tumor MeSH
• Tumor Microenvironment physiology   MeSH
• Brain Neoplasms * pathology   metabolism   MeSH
• Pericytes * metabolism   pathology   MeSH
• Cell Movement physiology   MeSH
• Serine Endopeptidases metabolism   MeSH
• Gelatinases metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH

Activation of microglia in the spinal cord dorsal horn after peripheral nerve injury contributes to the development of pain hypersensitivity. How activated microglia selectively enhance the activity of spinal nociceptive circuits is not well understood. We discovered that after peripheral nerve injury, microglia degrade extracellular matrix structures, perineuronal nets (PNNs), in lamina I of the spinal cord dorsal horn. Lamina I PNNs selectively enwrap spinoparabrachial projection neurons, which integrate nociceptive information in the spinal cord and convey it to supraspinal brain regions to induce pain sensation. Degradation of PNNs by microglia enhances the activity of projection neurons and induces pain-related behaviors. Thus, nerve injury-induced degradation of PNNs is a mechanism by which microglia selectively augment the output of spinal nociceptive circuits and cause pain hypersensitivity.

• MeSH
• Pain * pathology   physiopathology   MeSH
• Extracellular Matrix pathology   MeSH
• Hyperalgesia * etiology   pathology   physiopathology   MeSH
• Rats MeSH
• Microglia * pathology   MeSH
• Peripheral Nerve Injuries * complications   pathology   MeSH
• Rats, Sprague-Dawley MeSH
• Spinal Cord Dorsal Horn * pathology   physiopathology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Cells have developed a unique set of molecular mechanisms that allows them to probe mechanical properties of the surrounding environment. These systems are based on deformable primary mechanosensors coupled to tension transmitting proteins and enzymes generating biochemical signals. This modular setup enables to transform a mechanical load into more versatile biochemical information. Src kinase appears to be one of the central components of the mechanotransduction network mediating force-induced signalling across multiple cellular contexts. In tight cooperation with primary sensors and the cytoskeleton, Src functions as an effector molecule necessary for transformation of mechanical stimuli into biochemical outputs executing cellular response and adaptation to mechanical cues.

• MeSH
• Adaptor Proteins, Signal Transducing genetics   metabolism   MeSH
• Mechanotransduction, Cellular genetics   MeSH
• Cytoskeleton metabolism   pathology   ultrastructure   MeSH
• Extracellular Matrix metabolism   pathology   ultrastructure   MeSH
• Integrins genetics   metabolism   MeSH
• Humans MeSH
• Stress, Mechanical MeSH
• Neoplasms genetics   metabolism   pathology   MeSH
• Protein Serine-Threonine Kinases genetics   metabolism   MeSH
• Gene Expression Regulation MeSH
• src-Family Kinases genetics   metabolism   MeSH
• Crk-Associated Substrate Protein genetics   metabolism   MeSH
• Transcription Factors genetics   metabolism   MeSH
• Receptor-Like Protein Tyrosine Phosphatases, Class 4 genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease.

• MeSH
• Cell Differentiation genetics   MeSH
• Genome-Wide Association Study MeSH
• Extracellular Matrix metabolism   pathology   MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Loci * MeSH
• Risk Assessment MeSH
• Polymorphism, Single Nucleotide * MeSH
• Keratoconus diagnosis   ethnology   genetics   metabolism   MeSH
• Collagen metabolism   MeSH
• Humans MeSH
• Risk Factors MeSH
• Case-Control Studies MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Geographicals
• Australia MeSH
• Europe MeSH

Excessive connective tissue accumulation, a hallmark of hypertrophic scaring, results in progressive deterioration of the structure and function of organs. It can also be seen during tumor growth and other fibroproliferative disorders. These processes result from a wide spectrum of cross-talks between mesenchymal, epithelial and inflammatory/immune cells that have not yet been fully understood. In the present review, we aimed to describe the molecular features of fibroblasts and their interactions with immune and epithelial cells and extracellular matrix. We also compared different types of fibroblasts and their roles in skin repair and regeneration following burn injury. In summary, here we briefly review molecular changes underlying hypertrophic scarring following burns throughout all basic wound healing stages, i.e. during inflammation, proliferation and maturation.

• MeSH
• Epithelial Cells metabolism   pathology   MeSH
• Extracellular Matrix metabolism   pathology   MeSH
• Fibroblasts metabolism   pathology   MeSH
• Wound Healing genetics   MeSH
• Cicatrix, Hypertrophic genetics   immunology   pathology   MeSH
• Humans MeSH
• Burns genetics   pathology   MeSH
• Cell Proliferation genetics   MeSH
• Inflammation genetics   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

3D cell culture methods have been an integral part of and an essential tool for mammary gland and breast cancer research for half a century. In fact, mammary gland researchers, who discovered and deciphered the instructive role of extracellular matrix (ECM) in mammary epithelial cell functional differentiation and morphogenesis, were the pioneers of the 3D cell culture techniques, including organoid cultures. The last decade has brought a tremendous increase in the 3D cell culture techniques, including modifications and innovations of the existing techniques, novel biomaterials and matrices, new technological approaches, and increase in 3D culture complexity, accompanied by several redefinitions of the terms "3D cell culture" and "organoid". In this review, we provide an overview of the 3D cell culture and organoid techniques used in mammary gland biology and breast cancer research. We discuss their advantages, shortcomings and current challenges, highlight the recent progress in reconstructing the complex mammary gland microenvironment in vitro and ex vivo, and identify the missing 3D cell cultures, urgently needed to aid our understanding of mammary gland development, function, physiology, and disease, including breast cancer.

• MeSH
• Cell Differentiation MeSH
• Cell Culture Techniques instrumentation   MeSH
• Spheroids, Cellular pathology   MeSH
• Epithelial Cells pathology   MeSH
• Extracellular Matrix pathology   MeSH
• Coculture Techniques methods   MeSH
• Humans MeSH
• Mammary Glands, Human cytology   pathology   MeSH
• Mammary Glands, Animal cytology   pathology   MeSH
• Models, Animal MeSH
• Mice MeSH
• Breast Neoplasms pathology   MeSH
• Organoids MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

Hapln4 is a link protein which stabilizes the binding between lecticans and hyaluronan in perineuronal nets (PNNs) in specific brain regions, including the medial nucleus of the trapezoid body (MNTB). The aim of this study was: (1) to reveal possible age-related alterations in the extracellular matrix composition in the MNTB and inferior colliculus, which was devoid of Hapln4 and served as a negative control, (2) to determine the impact of the Hapln4 deletion on the values of the ECS diffusion parameters in young and aged animals and (3) to verify that PNNs moderate age-related changes in the ECS diffusion, and that Hapln4-brevican complex is indispensable for the correct protective function of the PNNs. To achieve this, we evaluated the ECS diffusion parameters using the real-time iontophoretic method in the selected region in young adult (3 to 6-months-old) and aged (12 to 18-months-old) wild type and Hapln4 knock-out (KO) mice. The results were correlated with an immunohistochemical analysis of the ECM composition and astrocyte morphology. We report that the ECM composition is altered in the aged MNTB and aging is a critical point, revealing the effect of Hapln4 deficiency on the ECS diffusion. All of our findings support the hypothesis that the ECM changes in the MNTB of aged KO animals affect the ECS parameters indirectly, via morphological changes of astrocytes, which are in direct contact with synapses and can be influenced by the ongoing synaptic transmission altered by shifts in the ECM composition.

• MeSH
• Trapezoid Body metabolism   pathology   MeSH
• Diffusion * MeSH
• Extracellular Matrix Proteins deficiency   MeSH
• Extracellular Matrix metabolism   pathology   MeSH
• Extracellular Space metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Protein Deficiency metabolism   pathology   MeSH
• Organ Culture Techniques MeSH
• Peripheral Nerves metabolism   pathology   MeSH
• Nerve Tissue Proteins deficiency   MeSH
• Auditory Pathways metabolism   pathology   MeSH
• Aging metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH