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At least 19 recordsLinked to original sources
PubMed2026

Macrophage regulation of extracellular matrix remodeling in aging skeletal muscle.

The extracellular matrix (ECM) is a dynamic structural network that supports tissue architecture and regulates cell function. It is primarily composed of collagens, elastin, proteoglycans, and glycoproteins, which are synthesized by canonical and non-canonical ECM-producing cells. During aging, the ECM undergoes progressive changes in structure and composition, a process recently recognized as the 13th hallmark of aging. In skeletal muscle (SKM), age-associated ECM remodeling, largely regulated by immune system-ECM crosstalk, contributes to sarcopenia and impaired regeneration. Macrophages (MΦs), as key innate immune cells, regulate ECM dynamics both indirectly by activating canonical ECM-producing cells and directly by synthesizing ECM components. Notably, a distinct subset of ECM-producing MΦs that express collagen (COL+ MΦs) has been identified across multiple tissues, although their function in SKM homeostasis and aging remains poorly understood. Here, we review current knowledge of ECM production and remodeling, with special emphasis on MΦ involvement, including COL+ MΦs, as critical regulators of fibrogenesis, especially during SKM aging and regeneration.

Extracellular Matrix↗
PubMed2026

Desmoplakin loss in alveolar epithelium drives Wnt/β-Catenin-mediated extracellular matrix remodeling and fibrotic signaling in vitro.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease characterized by aberrant extracellular matrix (ECM) remodeling, epithelial dysfunction, and limited therapeutic options. Genetic studies implicate Desmoplakin (DSP), a desmosomal adhesion protein, in IPF susceptibility; however, its mechanistic role remains unclear. This study aimed to investigate the role of DSP in regulating fibrotic and ECM remodeling pathways in alveolar epithelial cells. METHODS AND RESULTS: DSP was silenced using siRNA in adenocarcinoma-derived human alveolar epithelial A549 cells. DSP loss induced epithelial-to-mesenchymal transition, enhanced cell migration, and increased epithelial permeability, along with upregulation of fibrotic and ECM-associated genes. Pathway enrichment analysis of DSP interactors (STRING database) identified the Wnt/β-catenin signaling as a potential key pathway. Mechanistic validation using cycloheximide chase assays, qPCR, western blotting, immunofluorescence, and luciferase-reporter assays suggested that DSP loss destabilizes desmosomal complexes, promoting plakoglobin (γ-catenin) degradation while reducing β-catenin turnover. This was associated with increased nuclear accumulation of β-catenin and enhanced TCF/LEF-dependent transcription, leading to elevated expression of ECM-related genes, including COL1A1 and MMP9. DSP overexpression suppressed Wnt/β-catenin signaling and fibrotic gene expression, while pharmacological inhibition of this pathway attenuated DSP-dependent increases in ECM-associated gene expression. CONCLUSION: These findings suggest that DSP may function as a regulator of alveolar epithelial homeostasis and extracellular matrix remodeling in an in vitro epithelial model. Loss of DSP is associated with activation of Wnt/β-catenin-mediated fibrotic signaling, correlating with reduced plakoglobin stability. This study provides mechanistic insight into epithelial-matrix crosstalk in vitro and identifies a candidate pathway that may contribute to ECM dysregulation in IPF, the disease relevance of which will require validation in primary human alveolar epithelial cells and in vivo models.

Humans↗
PubMed1979

Ultrastructural and biochemical study of extracellular matrix vesicles in normal alveolar bone of rats.

The occurrence of vesicles in the extracellular matrix of alveolar bone of normal young rats was demonstrated by both ultrastructural and enzymatic studies. Transmission electron microscopy revealed abundant vesicles in the matrix. The presence of hydroxyapatite crystals, both within the vesicles and in the matrix, was affiliated with rupture of the vesicular membrane. Calcifying nodules were scarce. High levels of both specific and total activities of alkaline- and pyrophosphatases were found in the fraction of isolated vesicles. This fraction also showed activities of different ATPases and acid phosphatase.

Acid Phosphatase↗
PubMedDate not supplied

Newer knowledge of skeletogenesis: macromolecular transitions in the extracellular matrix.

Morphogenesis of skeletal tissues is accompanied by dramatic changes in the types and amounts of extracellular macromolecules synthesized. These changes correlate with the morphological and structural characteristics of each tissue type involved in skeletogenesis, viz. mesenchyme, cartilage and bone. At the beginning of skeletogenesis, a hyaluronate-rich extracellular matrix may provide a beneficial milieu for mesenchymal cell migration and proliferation, and prevent precocious differentiation. This matrix also contains type I collagen and possibly a unique sulfated proteoglycan. Cartilage differentiation, during endochondral osteogenesis, involves the removal of hyaluronate and the production of large amounts of type II collagen and a characteristic chondroitin sulfate-proteoglycan. Further complex transitions in arrangement and concentration of proteoglycan occur in the epiphyseal growth plate followed by sudden depletion at the site of initiation of bone formation. In addition, at this site, the type of collagen synthesized reverts from type II back to type I. Bone formation at periosteal sites also involves removal of proteoglycan. The collagen component of both osteoid and bone matrix is type I but the level of hydroxylation of lysine moieties may be significantly higher in osteoid. It is proposed that changes in extracellular matrix composition are important factors in the control of morphogenesis as well as in providing suitable structural properties to the developing skeletal tissues.

Animals↗
PubMed1977

Failure of cultured chick embryo fibroblasts to incorporate collagen into their extracellular matrix when transformed by Rous sarcoma virus. An effect of transformation but not of virus production.

Whole chick embryo fibroblasts were infected with the Prague wild type Rous sarcoma virus and with a temperature sensitive mutant of this strain, RSVtsLA24. Normal fibroblasts and fibroblasts infected with the temperature-sensitive mutant and cultured at the nonpermissive temperature-sensitive mutant and cultured at the nonpermissive temperature, secreted procollagen into the medium and incorporated collagen into their extracellular matrix. On the other hand, transformed fibroblasts and fibroblasts infected with the temperature-sensitive mutant and cultured at the permissive temperature, were able to secrete procollagen into the medium, but there was no evidence that they were able to convert procollagen to collagen and incorporate collagen into an extracellular matrix. The inability of the infected cells to incorporate collagen into an extracellular matrix was found to be a result of transformation rather than of virus production in these cells.

Animals↗
PubMed2026

Tissue-derived extracellular matrix hydrogels instruct epigenetic adaptation in metastatic colonization.

The extracellular matrix (ECM) plays a central role in regulating tumor progression and metastatic colonization by providing biochemical and mechanical signals that shape cancer cell fate. However, most organoid culture systems rely on basement membrane extracts that fail to reproduce the tissue-specific extracellular environments encountered during metastasis. Here, we develop tissue-derived decellularized matrix hydrogels to reconstruct organ-specific microenvironments and investigate epigenetic adaptation to ECM cues during metastatic colonization. Patient-derived colorectal cancer organoids cultured in colon-derived matrices exhibited enhanced maintenance of stem-like phenotypes and colon-specific chromatin accessibility landscapes compared with cultures grown in basement membrane extracts, demonstrating improved physiological relevance for primary tumor modeling. When exposed to matrices derived from secondary organs, the organoids showed distinct growth phenotypes accompanied by rapid, tissue-dependent chromatin accessibility remodeling, indicating that ECM composition alone can reshape regulatory programs governing metastatic adaptation. Notably, liver-derived matrices selectively activated hepatocyte nuclear factor 4 alpha (HNF4A)-associated transcriptional networks and created a context-specific dependence on c-MET signaling for survival. Functional perturbation of HNF4A or c-MET signaling confirmed that both are required for organoid formation specifically within the liver matrix environment. Together, these findings establish tissue-derived matrix hydrogels as instructive bioactive materials that actively regulate cancer cell epigenetic states and reveal microenvironment-specific therapeutic vulnerabilities during early metastatic colonization.

Journal Article↗
PubMed2025

Understanding proneural-mesenchymal transition using patient-derived glioma stem-like cell (GSC) organoids and engineered extracellular matrix.

Glioblastoma multiforme (GBM) is a highly aggressive, angiogenic WHO grade IV glioma marked by rapid progression, therapeutic resistance, and poor prognosis. A defining feature of GBM is the presence of glioma stem-like cells (GSCs), which reside in specialized perivascular niches and drive tumor progression, recurrence, and therapeutic resistance. The blood-brain barrier, coupled with the complex and dynamic tumor microenvironment, poses significant challenges for both treatment and mechanistic investigation. Current in vitro GBM models inadequately recapitulate the structural and biochemical cues of the native perivascular niche due to the absence of functional vasculature and brain-mimetic extracellular matrix (ECM), limiting their physiological relevance and predictive power. To address the limitations of existing in vitro GBM models, we developed a patient-derived glioma stem cells (GSC) derived Matrigel spheroid system that transitions into organoids and enables integration into engineered microenvironments. Our model incorporates GSC organoids representing proneural and mesenchymal GBM subtypes, a synthetic engineered extracellular matrix (eECM), and endothelial cells (ECs) seeded on the matrix surface. We evaluated the expression of subtype-specific, pro-angiogenic, stemness, and differentiation markers under increasingly complex co-culture conditions. Our results show that Matrigel-derived GSC spheroids progressively differentiate into organoids over two weeks, with significantly enhanced expression of cell-specific markers in the presence of ECs. Encapsulation of these organoids within eECM, combined with EC co-culture, further promoted cellular invasion and induction of GBM associated genes. This in situ encapsulation strategy enables real-time observation of GSC behavior in a tunable microenvironment that mimics key features of the native tumor niche. Together, this platform provides a physiologically relevant and modular in vitro system for investigating GBM pathophysiology. It holds promise for uncovering tumor-specific cellular dependencies, studying GSC-vascular interactions, and conducting high-throughput drug screening under controlled, biomimetic conditions.

Engineered extracellular matrix↗
PubMed1977

Extracellular matrix synthesis in blastula and gastrula stages of normal and hybrid frog embryos. I. Toluidine blue and lanthanum staining.

Four developmental stages of Rana pipiens, R. pipiens female X R. catesbeiana female, and R. pipiens female X R. esculenta male embryos were fixed in standard electron microscopic fixatives with or without 1% lanthanum nitrate (LN) added. Embryos fixed without LN were embedded and sectioned at 0-5 micrometer and stained with toluidine blue. Embryos fixed with LN were embedded and sectioned at 70-80 nm and examined in the electron microscope. Both techiques show a dramatic increase in the amount of stainable material in the extracellular matrix during development. Blastula stage embryos have a small amount of material in the extracellular matrix. Early gastrulae have more stainable material than blastulae and this increased amount appears to be due to an accumulation of material in the marginal zone of the embryo, especially near the dorsal lip of the blastopore. Late gastrulae have large amounts of stainable material in the extracellular spaces in almost all parts of the embryo. Interspecific arrested hybrid embryos do not show the same dramatic accumulation of stainable material in their extracellular matrices.

Animals↗
PubMed2026

Spatial Proteomics of the Human Atherosclerotic Microenvironment Reveals Heterogeneity in Intraplaque Proteomes and Extracellular Matrix Remodeling.

Plaque heterogeneity underlies the propensity of atherosclerotic lesions to rupture and trigger cardiovascular events. Most proteomic studies examine bulk changes, obscuring key spatial differences in protein abundance. We report a high-resolution spatial proteomics workflow exploring the molecular landscape of human plaques and a murine myocardium. By combining laser capture microdissection with high-sensitivity ion-mobility mass spectrometry, spatial profiling of cellular and extracellular matrix (ECM) proteomes was achieved. Over 2700 proteins were detected from 50,000 μm2 areas, revealing substantial intraplaque heterogeneity across distinct regions (lipid-rich, media, shoulder, necrotic core, intima) and distance from the artery lumen. Inverse correlations between proteases (cathepsin B) and core structural ECM proteins (perlecan, HSPG2) indicated active ECM remodeling. Analysis of media layers indicated distinct protein signatures associated with smooth muscle contraction and cell-cell communication. Blood coagulation signatures, including platelet degranulation and fibrin formation, were enriched at the intima. Inflammatory (clusters of differentiation 4/68, CD4/CD68; vascular cell adhesion molecule 1, VCAM1) and vascular damage markers (tenascin-C, TNC) were enriched in shoulder regions. The necrotic core was dominated by blood proteins, consistent with intraplaque hemorrhage. This workflow resolves proteomic changes over ∼200 μm distances, providing unprecedented insights into plaque morphology and offers a powerful tool for elucidating plaque biology.

Humans↗
PubMed2024

Proteomic Heterogeneity of the Extracellular Matrix Identifies Histologic Subtype-Specific Fibroblast in Gastric Cancer.

Gastric cancer (GC) is a highly heterogeneous disease regarding histologic features, genotypes, and molecular phenotypes. Here, we investigate extracellular matrix (ECM)-centric analysis, examining its association with histologic subtypes and patient prognosis in human GC. We performed quantitative proteomic analysis of decellularized GC tissues that characterizes tumorous ECM, highlighting proteomic heterogeneity in ECM components. We identified 20 tumor-enriched proteins including four glycoproteins, serpin family H member 1 (SERPINH1), annexin family (ANXA3/4/5/13), S100A family (S100A6/8/9), MMP14, and other matrisome-associated proteins. In addition, histopathological characteristics of GC reveals differential expression in ECM composition, with the poorly cohesive carcinoma-not otherwise specified (PCC-NOS) subtype being distinctly demarcated from other histologic subtypes. Integrating ECM proteomics with single-cell RNA sequencing, we identified crucial molecular markers in the PCC-NOS-specific stroma. PCC-NOS-enriched matrisome proteins and gene expression signatures of adipogenic cancer-associated fibroblasts (CAFadi) are closely linked, both associated with adverse outcomes in GC. Using tumor microarray analysis, we confirmed the CAFadi surface marker, ATP binding cassette subfamily A member 8 (ABCA8), predominantly present in PCC-NOS tumors. Our ECM-focused analysis paves the way for studies to determine their utility as biomarkers for patient stratification, offering valuable insights for linking molecular and histologic features in GC.

Humans↗
PubMed2026

The multilayered cuticle underlying structural coloration in red algae shares features with the metazoan extracellular matrix.

Structural coloration, a physical phenomenon observed in many living organisms, may arise from the interference of light with highly organized surface nanostructures. In some seaweeds, these nanostructures consist of cuticular lamellae in the outer part of the extracellular matrix (ECM) of the epidermis. However, the chemical composition of seaweed cuticles is poorly understood and the molecular components of lamellae remain unidentified. Here, we use integrated genomic, transcriptomic, proteomic, and metabolomic approaches together with analytical profiling of carbohydrates to determine the composition of the multilayered cuticle in the red alga Chondrus crispus and assess its evolutionary conservation. The structural assembly reveals common features with the ECM of animals. The carbohydrate fraction includes a complex mixture of carrageenans and glycosaminoglycan-like compositions. A major von Willebrand factor A domain protein, Lamellae Cohesive Protein, plays a critical role in protein-protein interactions and binding to sulfated polysaccharides. We have further identified the major proteins of the algal cuticle, providing a framework for addressing the evolutionary origins of the cuticle and raising important questions regarding its role, particularly across the red algal life cycle marked by major structural differences in its ECM.

Extracellular Matrix↗
PubMed2026

FOS Regulates Myogenic and Adipogenic Differentiation via Extracellular Matrix Signaling.

In the livestock industry, intramuscular fat deposition is a key factor influencing meat tenderness and flavor. Although FOS (Fos proto-oncogene, AP-1 transcription factor subunit) has been implicated in the regulation of cell proliferation and differentiation, its differential roles in myogenic and adipogenic regulation remain unclear. In this study, we revealed that FOS markedly enhanced myogenic differentiation while inhibiting adipogenic differentiation in muscle stem cells, indicating that it exerts distinct effects on muscle development and intramuscular fat deposition. Mechanistically, FOS modulated extracellular matrix signaling by regulating FAK and PXN phosphorylation, acting as a molecular regulator between the muscle and fat lineages. Furthermore, exon SNPs in FOS were associated with slaughter weight and backfat thickness, and the mutant genotypes weakened its antiadipogenic effect. Collectively, these findings suggest that FOS is an important regulator of myogenic and adipogenic differentiation and is a potential candidate gene for the genetic improvement of meat quality traits.

Animals↗
PubMed1975

Ultrastructural identification of extracellular matrix and cell surface components during limb morphogenesis in man.

Development of the human hand plate (stages 16-17) has been analyzed with emphasis on differentiation of elements within the extracellular matrix and the composition of the mesenchymal cell surface. The epithelial-mesenchymal interface contains a basal lamina and a sublaminar matrix exhibiting: (a) collagen fibrils with characteristic 63-64 nm banding: (b) non-banded filaments, 10-15 nm in diameter; (c) ruthenium red-positive particles, 12-15 nm in diameter; and (d) attenuated threads, 3-5-5-0 nm in diameter which inter-connect particles, fibrils, filaments and the basal lamina. Processes of mesenchymal cells penetrate this matrix network. In addition to staining with ruthenium red, components of basal laminae bind to ferritin-conjugated Concanavalin A, greatest binding being localized on the mesenchymal surface of the lamina. Asymmetry of binding is removed by incubation of exposed laminae with trypsin (5 mug/ml). Regional differences in these staining and binding characteristics within the subepithelial matrix have not been observed in the hand plate. However, precartilaginous extracellular zones deep within the plate are notably unstructured in comparison to the sublaminar region. Ruthenium red-positive materials at mesenchymal cell surfaces display sensitivity to testicular hyaluronidase, Pronase and trypsin but resist removal with neuraminidase and EDTA. These features of the substrate in situ may be important in the regulation of mesenchymal cell behavior during limb morphogenesis in man.

Binding Sites↗
PubMed1979

The relationship between extracellular matrix vesicles and calcospherities in primary mineralization of neoplastic bone tissue. TEM and SEM studies on osteosarcoma.

Primary mineralization in neoplastic tissue was studied in osteosarcoma, correlating observations obtained by SEM to those found with TEM. The process is characterized by extracellular matrix vesicles, distributed in the matrix between the forming neoplastic cells and the calcifying fronts. The occurrence of osmiophilic material and solitary hydroxyapatite crystals within the vesicles is followed by accumulation of apatite crystals, disappearance of the vesicular membrane and formation of calcospherites and calcified fronts. The process described here in neoplastic tissue is essentially similar to primary calcification in normal calcified tissues.

Apatites↗
PubMed2025

Intratumoral fungus Neurospora crassa is associated with worsened prognosis in ovarian cancer via modulation of extracellular matrix.

Landmark studies on intratumoral fungi (ITF) have raised concerns due to irreproducible results and data-analysis errors. We aimed to determine whether ITF exist in ovarian cancer (OvCa) and, if so, whether they play a role in disease biology. Formalin-fixed, paraffin-embedded OvCa samples and multiple controls underwent operational decontamination, qPCR, internal transcribed spacer sequencing, and post-hoc data decontamination. We also leveraged updated fungal reads from The Cancer Genome Atlas generated by the TCMbio group, which addressed human-read contamination and artificial inflation, to validate findings and assess prognostic associations. A murine syngeneic model established using mouse ovarian cancer cell line (OVHM) with intratumoral Neurospora crassa injection was established. Transcriptomic and metabolomic analyses were performed to explore mechanisms. Tumor-containing blocks harbored significantly higher fungal loads than environmental controls but had loads comparable to paraffin controls. Applying a two-pass decontamination filter reduced raw sequence features from 9289 amplicon sequence variants (ASVs) to 659 ASVs. We focused on high-abundance features present in human tissues but absent from xenografts and paraffin controls and identified one candidate, N. crassa, associated with unfavorable prognosis in OvCa. Integrating human and murine data, we found Neurospora correlated with eosinophils, whereas N. crassa itself was not immune-related. Neurospora crassa promoted OvCa progression with downregulation of integrin-linked kinase and decreased extracellular matrix-receptor interaction. Most ITF signals are likely contaminants. We identified N. crassa as associated with unfavorable prognosis in OvCa, potentially via modulation of the extracellular matrix.

Neurospora crassa↗
PubMed1979

Distribution of fetal bovine serum fibronectin and endogenous rat cell fibronectin in extracellular matrix.

Normal rat kidney cells were cultured in medium supplemented with normal fetal bovine serum (FBS) or FBS depleted of fibronectin. The cell surface fibronectin of these cultures was visualized by indirect immunofluorescence using species-specific antisera for either rat fibronectin or bovine fibronectin. Anti-rat-fibronectin revealed fibrillar structures on the cells grown in either normal medium or fibronectin-depleted medium. Anti-bovine fibronectin revealed similar fibrillar networks, but only on the cells grown in medium containing bovine fibronectin. Staining in each case was abolished by absorption with the homologous antigen. It appears that exogenous fibronectin was incorporated into the same structures as endogenous fibronectin. This finding suggests that circulating fibronectin may serve as a building block for the assembly of extracellular matrix, possibly by cells which are incapable of synthesizing it.

Animals↗
PubMed2026

The extracellular matrix in cancer-associated fibrosis: molecular mechanisms and clinical relevance.

The ECM is a dynamic component of the tumor microenvironment with a critical role in cancer progression, invasion, metastasis, immune exclusion, and response to therapy. Recent advances in proteomic analyses investigating the insoluble ECM fractions (termed "matrisome analysis"), along with single-cell RNA sequencing and spatial transcriptomics, have revealed cancer-specific patterns of ECM remodeling. These studies have identified a panel of recurrently upregulated ECM proteins, including annexin A1, fibrillin-1, fibronectin, periostin, and tenascin-C, actively contributing to tumor growth, invasion, angiogenesis, and immune exclusion. The expression of the cancer-associated ECM is largely driven by cancer-associated fibroblasts (CAFs), whose molecular diversity has been dissected through single-cell profiling and consolidated in emerging CAF atlases across cancers. By investigating the matrisome composition and CAF heterogeneity, these studies have unraveled the pivotal role of the stroma in shaping tumor biology. Based on these discoveries, ECM proteins and CAFs are now being explored as biomarkers and therapeutic targets. Future integration of multi-omics datasets with clinical outcomes will help to translate these insights into novel biomarkers for patient stratification and stroma-directed therapeutic interventions.

Humans↗
PubMed2025

Proteomics of Duchenne Muscular Dystrophy Patient iPSC-Derived Skeletal Muscle Cells Reveal Differential Expression of Cytoskeletal and Extracellular Matrix Proteins.

Proteomics of dystrophic muscle samples is limited by the amount of protein that can be extracted from patient biopsies. Cells and tissues derived from patient-derived induced pluripotent stem cells (iPSCs) can be an expandable alternative source. We have patterned iPSCs from three Duchenne muscular dystrophy (DMD) patient lines into skeletal muscle cells using a two-dimensional as well as our three-dimensional organoid differentiation system. Probes with sufficient protein amounts could be extracted and prepared for mass spectrometry. In total, 3007 proteins in 2D and 2709 proteins in 3D were detected in DMD patient probes. A total of 83 proteins in 2D and 338 proteins in 3D can be described as differentially expressed between DMD and control patient probes in a post hoc test. We have identified and we propose Myosin-9, Collagen 18A, Tropomyosin 1, BASP1, RUVBL1, and NCAM1 as proteins specifically altered in their expression in DMD for further investigation. Proteomics of skeletal muscle organoids resulted in greater consistency of results between cell lines in comparison to the two-dimensional myogenic differentiation protocol.

Humans↗