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The process of aging is intimately linked to alterations at the tissue and cellular levels. Currently, the role of senescent cells in the tissue microenvironment is still being investigated. Despite common characteristics, different cell populations undergo distinctive morphofunctional changes during senescence. Mesenchymal stem cells (MSCs) play a pivotal role in maintaining tissue homeostasis. A multitude of studies have examined alterations in the cytokine profile that determine their regulatory function. The extracellular matrix (ECM) of MSCs is a less studied aspect of their biology. It has been shown to modulate the activity of neighboring cells. Therefore, investigating age-related changes in the MSC matrisome is crucial for understanding the mechanisms of tissue niche ageing. This study conducted a broad proteomic analysis of the matrisome of separated fractions of senescent MSCs, including the ECM, conditioned medium (CM), and cell lysate. This is the first time such an analysis has been conducted. It has been established that there is a shift in production towards regulatory molecules and a significant downregulation of the main structural and adhesion proteins of the ECM, particularly collagens, fibulins, and fibrilins. Additionally, a decrease in the levels of cathepsins, galectins, S100 proteins, and other proteins with cytoprotective, anti-inflammatory, and antifibrotic properties has been observed. However, the level of inflammatory proteins and regulators of profibrotic pathways increases. Additionally, there is an upregulation of proteins that can directly cause prosenescent effects on microenvironmental cells (SERPINE1, THBS1, and GDF15). These changes confirm that senescent MSCs can have a negative impact on other cells in the tissue niche, not only through cytokine signals but also through the remodeled ECM. [ABSTRACT FROM AUTHOR]

The hepatic matrisome is involved in the remodeling phase of liver regeneration. As the gut microbiota has been implicated in liver regeneration, we investigated its role in liver regeneration focusing on gene expression of the hepatic matrisome after partial hepatectomy (PHx) in germ-free (GF) mice, and in GF mice reconstituted with normal gut microbiota (XGF). Liver mass restoration, hepatocyte proliferation, and immune response were assessed following 70% PHx. Hepatic matrisome and collagen gene expression were also analyzed. Reduced liver weight/body weight ratio, mitotic count, and hepatocyte proliferative index at 72 h post PHx in GF mice were preceded by reduced expression of cytokine receptor genes Tnfrsf1a and Il6ra, and Hgf gene at 3 h post PHx. In XGF mice, these indices were significantly higher than in GF mice, and similar to that of control mice, indicating normal liver regeneration. Differentially expressed genes (DEGs) of the matrisome were lower in GF compared to XGF mice at both 3 h and 72 h post PHx. GF mice also demonstrated lower collagen expression, with significantly lower expression of Col1a1, Col1a2, Col5a1, and Col6a2 compared to WT mice at 72 h post PHx. In conclusion, enhanced liver regeneration and matrisome expression in XGF mice suggests that interaction of the gut microbiota and matrisome may play a significant role in the regulation of hepatic remodeling during the regenerative process. [ABSTRACT FROM AUTHOR]

Precise characterization of a tissue's extracellular matrix (ECM) protein composition (matrisome) is essential for biomedicine. However, ECM protein extraction that requires organ-specific optimization is still a major limiting factor in matrisome studies. In particular, the matrisome of mouse kidneys is still understudied, despite mouse models being crucial for renal research. Here, we comprehensively characterized the matrisome of kidneys in healthy C57BL/6 mice using two ECM extraction methods in combination with liquid chromatography tandem mass spectrometry (LC-MS/MS), protein identification, and label-free quantification (LFQ) using MaxQuant. We identified 113 matrisome proteins, including 22 proteins that have not been previously listed in the Matrisome Database. Depending on the extraction approach, the core matrisome (structural proteins) comprised 45% or 73% of kidney ECM proteins, and was dominated by glycoproteins, followed by collagens and proteoglycans. Among matrisome-associated proteins, ECM regulators had the highest LFQ intensities, followed by ECM-affiliated proteins and secreted factors. The identified kidney ECM proteins were primarily involved in cellular, developmental and metabolic processes, as well as in molecular binding and regulation of catalytic and structural molecules' activity. We also performed in silico comparative analysis of the kidney matrisome composition in humans and mice based on publicly available data. These results contribute to the first reference database for the mouse renal matrisome. [ABSTRACT FROM AUTHOR]

Tumor cell infiltrative ability into surrounding brain tissue is a characteristic of diffusely infiltrative astrocytoma and is strongly associated with extracellular matrix (ECM) stiffness. Collagens are the most abundant ECM scaffolding proteins and contribute to matrix organization and stiffness. LOX family members, copper-dependent amine oxidases, participate in the collagen and elastin crosslinking that determine ECM tensile strength. Common IDH mutations in lower-grade gliomas (LGG) impact prognosis and have been associated with ECM stiffness. We analyzed the expression levels of LOX family members and matrisome-associated genes in astrocytoma stratified by malignancy grade and IDH mutation status. A progressive increase in expression of all five LOX family members according to malignancy grade was found. LOX, LOXL1, and LOXL3 expression correlated with matrisome gene expressions. LOXL1 correlations were detected in LGG with IDH mutation (IDHmut), LOXL3 correlations in LGG with IDH wild type (IDHwt) and strong LOX correlations in glioblastoma (GBM) were found. These increasing correlations may explain the increment of ECM stiffness and tumor aggressiveness from LGG-IDHmut and LGG-IDHwt through to GBM. The expression of the mechanosensitive transcription factor, β-catenin, also increased with malignancy grade and was correlated with LOXL1 and LOXL3 expression, suggesting involvement of this factor in the outside–in signaling pathway. [ABSTRACT FROM AUTHOR]

Matrix remodeling could be an important mode of action of multipotent mesenchymal stromal cells (MSC) in extracellular matrix (ECM) disease, but knowledge is limited in this respect. As MSC are well-known to adapt their behavior to their environment, we aimed to investigate if their mode of action would change in response to healthy versus pathologically altered ECM. Human MSC-derived ECM was produced under different culture conditions, including standard culture, culture on Matrigel-coated dishes, and stimulation with the pro-fibrotic transforming growth factor-β1 (TGFβ1). The MSC-ECM was decellularized, characterized by histochemistry, and used as MSC culture substrate reflecting different ECM conditions. MSC were cultured on the different ECM substrates or in control conditions for 2 days. Culture on ECM increased the presence of surface molecules with ECM receptor function in the MSC, demonstrating an interaction between MSC and ECM. In MSC cultured on Matrigel-ECM and TGFβ1-ECM, which displayed a fibrosis-like morphology, gene expression of collagens and decorin, as well as total matrix metalloproteinase (MMP) activity in the supernatant were decreased as compared with control conditions. These results demonstrated that MSC adapt to their ECM environment, which may include pathological adaptations that could compromise therapeutic efficacy. [ABSTRACT FROM AUTHOR]

The expression and regulation of matrisome genes—the ensemble of extracellular matrix, ECM, ECM-associated proteins and regulators as well as cytokines, chemokines and growth factors—is of paramount importance for many biological processes and signals within the tumor microenvironment. The availability of large and diverse multi-omics data enables mapping and understanding of the regulatory circuitry governing the tumor matrisome to an unprecedented level, though such a volume of information requires robust approaches to data analysis and integration. In this study, we show that combining Pan-Cancer expression data from The Cancer Genome Atlas (TCGA) with genomics, epigenomics and microenvironmental features from TCGA and other sources enables the identification of "landmark" matrisome genes and machine learning-based reconstruction of their regulatory networks in 74 clinical and molecular subtypes of human cancers and approx. 6700 patients. These results, enriched for prognostic genes and cross-validated markers at the protein level, unravel the role of genetic and epigenetic programs in governing the tumor matrisome and allow the prioritization of tumor-specific matrisome genes (and their regulators) for the development of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) provides structural support for tissue architecture and is a major effector of cell behavior during skin repair and inflammation. Macrophages are involved in all stages of skin repair but only limited knowledge exists about macrophage-specific expression and regulation of ECM components. In this study, we used transcriptome profiling and bioinformatic analysis to define the unique expression of ECM-associated genes in cultured macrophages. Characterization of the matrisome revealed that most genes were constitutively expressed and that several genes were uniquely regulated upon interferon gamma (IFNγ) and dexamethasone stimulation. Among those core matrisome and matrisome-associated components transforming growth factor beta (TGFβ)-induced, matrix metalloproteinase 9 (MMP9), elastin microfibril interfacer (EMILIN)-1, netrin-1 and gliomedin were also present within the wound bed at time points that are characterized by profound macrophage infiltration. Hence, macrophages are a source of ECM components in vitro as well as during skin wound healing, and identification of these matrisome components is a first step to understand the role and therapeutic value of ECM components in macrophages and during wound healing. [ABSTRACT FROM AUTHOR]