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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 February 2026 | Viewed by 4023

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Dr. Eric Huet

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Guest Editor

TRePCa—Therapeutic Resistance in Prostate Cancer, Université Paris-Est Créteil, 94010 Creteil, France
Interests: matrix biology; tumor microenvironment; matric metalloproteinases; extracellular vesicles; tissue remodeling; cell interactions; EMMPRIN
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Special Issue Information

Dear Colleagues,

As you well know, the extracellular matrix (ECM) represents a complex network of numerous multidomain macromolecules and cells organized in specific manners to form structurally stable structures, not only contributing to the mechanical properties of tissues but also representing an incredible reservoir of growth factors, bioactive molecules, enzymes, and extracellular vesicles. The ECM is of vital importance, extremely dynamic, thus controlling innumerable characteristics of cells, and numerous fundamental behaviors, such as proliferation, apoptosis, differentiation, adhesion, or migration.

In this Special Issue, original research and review articles on basic science, preclinical, and clinical findings are warmly welcome to contribute to our understanding of ECM and its impacts on physiopathology.

Dr. Eric Huet
Guest Editor

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Keywords

extracellular matrix
glycosaminoglycans
matrix metalloproteinases
tissue remodeling
cell interactions
physiopathology

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Published Papers (4 papers)

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Research

17 pages, 3427 KB

Open AccessArticle

Effects of Topography and Extracellular Matrix Composition on Focal Adhesion Patterning in Human Corneal Fibroblasts

by Divya Subramanian, Nathaniel S. Tjahjono, Tarik Z. Shihabeddin, Satweka Nammi, Miguel Miron-Mendoza, Victor D. Varner, W. Matthew Petroll and David W. Schmidtke

Int. J. Mol. Sci. 2025, 26(24), 11935; https://doi.org/10.3390/ijms262411935 - 11 Dec 2025

Abstract

Corneal fibroblasts adhere to the extracellular matrix via integrin-containing focal adhesions (FAs). Although topographical cues are known to influence FA patterning in corneal fibroblasts, it is unclear how ECM composition, biophysical cues, and specific integrins modulate FA patterning in corneal fibroblasts. In this study, we cultured a human corneal fibroblast cell line (HTKs) on different ECM proteins and micropatterns of aligned collagen fibrils to determine the effects of ECM topography and composition on focal adhesion subcellular patterning. Using confocal imaging, we observed and quantified changes in FA and integrin patterning based on the underlying ECM type. More specifically, the presence of fibrillar topography as compared to monomeric collagen resulted in diminished FA number, area, and length. Using specific integrin blocking antibodies, we also demonstrate that HTKs use different integrin subunits to adhere to specific ECM coatings. For example, β₁ integrins are important in adhesion formation when corneal fibroblasts adhere to collagen, while α₅ integrin is important for the HTKs to adhere to fibronectin. Blocking of α₅ integrin did not completely inhibit cell spreading and FA patterning when cells adhered to fibronectin. These results suggest that there might be other fibronectin receptors that HTKs use in the absence of α₅ integrin. These results lay the foundation to understand the role of different integrin subunits in FA patterning. Through further experimentation using our developed platform, we envision that a better understanding of the integrins and their associated signaling could have implications for advanced in vitro and in vivo applications in cornea biology. Full article

(This article belongs to the Special Issue The Extracellular Matrix in Physiopathology)

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26 pages, 3274 KB

Open AccessArticle

Unraveling the Matrix: Proteomic Profiling Reveals Stromal ECM Dysregulation in Severe Early-Onset Fetal Growth Restriction

by Stefano Ginocchio, Maxwell C. McCabe, Amanda R. Flockton, Diane L. Gumina, Kirk C. Hansen, Shuhan Ji and Emily J. Su

Int. J. Mol. Sci. 2025, 26(22), 11179; https://doi.org/10.3390/ijms262211179 - 19 Nov 2025

Viewed by 328

Abstract

An underdeveloped placental vasculature is a cardinal feature in severe, early-onset fetal growth restriction with absent/reversed umbilical artery Doppler end-diastolic velocities (FGR_a/r). Tissue microenvironment is a key mediator of angiogenesis; yet, the role of placental villous stromal extracellular matrix (ECM) in FGR_a/r remains unknown. We applied an ECM-optimized, proteomic workflow to villous tissue and placental fibroblast cell-derived matrices (CDM) from FGR_a/r, gestational age-matched controls, and uncomplicated term pregnancies. No significant differences were detected in villous tissue, although there was a trend toward increased type I collagen and fibronectin in FGR_a/r placentas. FGR_a/r CDM, however, appeared distinct from both control groups, with elevated matrisome abundance, greater insolubility of matrisome-associated proteins, and 44 differentially expressed matrisome proteins. Fibronectin emerged as a central network hub among differential matrisome proteins, interacting with thrombospondin-1, vitronectin, and transglutaminase-2, all of which were enriched in FGR_a/r CDM, suggesting excessive deposition and crosslinking. In contrast, regulators of ECM remodeling and TGFβ activity, including fibrillin-1, decorin, and syndecan-4, were depleted. These features suggest a pro-fibrotic, dysregulated stroma with diminished remodeling capacity. Our findings establish the first, comprehensive proteomic map of human placental stromal matrisome and provide a molecular framework for understanding how aberrant ECM organization contributes to placental dysfunction. Full article

(This article belongs to the Special Issue The Extracellular Matrix in Physiopathology)

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15 pages, 2875 KB

Open AccessArticle

Serial Combination of Toxic and Ischemic Renal Damages Causes Subsequent Chronic, Irreversible, and Progressive Renal Disease in Rats

by Giampiero A. Massaro, Joana Mercado-Hernández, Roel Broekhuizen, Tri Q. Nguyen, Isabel Fuentes-Calvo, Sandra M. Sancho-Martínez, Carlos Martínez-Salgado and Francisco J. López-Hernández

Int. J. Mol. Sci. 2025, 26(19), 9336; https://doi.org/10.3390/ijms26199336 - 24 Sep 2025

Viewed by 611

Abstract

Chronic kidney disease (CKD) poses a global burden affecting over 10% of the adult population worldwide. Acute kidney injury (AKI) is an important cause of CKD, especially following severe and repeated episodes. However, the processes underpinning progressive and chronic renal deterioration after AKI are only incompletely understood. Thus, models reproducing this scenario are needed to study the pathophysiological mechanisms involved and identify biomarkers and molecular targets for diagnostic and therapeutic purposes. In this study, we developed a rat model of 3 serial AKIs leading to CKD, in which renal function, kidney structure and fibrosis, and urinary injury biomarkers were studied over a period of 9 months, alongside a traditional model of CKD caused by renal mass reduction. Our results show that consecutive AKIs eventually develop key features of CKD including progressive fibrosis and albuminuria. Renal injury biomarkers neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and retinol binding protein 4 (RBP4) show distinct evolution patterns suggestive of specific but undetermined damages with different time courses. The chronic evolution of renal tissue degeneration and dysfunction following serial AKIs closely resembles those observed after extensive renal mass reduction, which indicates chronic degeneration. Finally, a clear dissociation in the evolution of interstitial fibrosis (progressively increasing) and of glomerular filtration (mainly stable) was observed in both models. This questions the consuetudinary paradigm ascribing an etiological role to fibrosis in progressive renal dysfunction. Full article

(This article belongs to the Special Issue The Extracellular Matrix in Physiopathology)

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16 pages, 2671 KB

Open AccessArticle

Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinases, and Their Ratios in Women with Polycystic Ovary Syndrome and Healthy Controls

by Alexandra E. Butler, Manjula Nandakumar, Thozhukat Sathyapalan, Edwina Brennan and Stephen L. Atkin

Int. J. Mol. Sci. 2025, 26(1), 321; https://doi.org/10.3390/ijms26010321 - 1 Jan 2025

Cited by 7 | Viewed by 2449

Abstract

Matrix metalloproteinases (MMPs) are M2 macrophage markers that are modulated by inflammation. A disintegrin and metalloproteinases (ADAMS) and those with thrombospondin motifs (ADAMTS) regulate the shedding of membrane-bound proteins, growth factors, cytokines, ligands, and receptors; MMPs, ADAMS, and ADAMTS may be regulated by tissue inhibitors of metalloproteinases (TIMPs). This study aimed to determine whether these interacting proteins were dysregulated in PCOS. A Somascan proteomic analysis of 12 MMPs, three of their inhibitors (TIMP-1, 2, 3), two ADAMS (9, 12), five ADAMTS (1, 4, 5, 13, 15), insulin-like growth factor binding protein-1 (IGFBP-1), and insulin-like growth factor-1 (IGF-1) was undertaken in a well-validated PCOS database of 143 women with PCOS and 97 controls. Women with PCOS had significantly higher levels of MMP-9 and lower levels of MMP-2, MMP-14, TIMP-2, IGFBP-1, and IGF-1 compared to the controls (p < 0.0001, p < 0.005, p < 0.04, p < 0.05, p < 0.0001, and p < 0.0001, respectively). No differences were observed for any other MMPs. The ADAMS or ADAMTS levels did not differ between groups. Body mass index (BMI) was correlated with MMP-9 (p < 0.01), MMP-1 (p < 0.05), MMP-2 (p < 0.05), MMP-10 (p < 0.005), MMP-12 (p < 0.005), ADAM-9 (p < 0.05), and IGFBP-1 (p < 0.0001), but only MMP-9 still differed after accounting for BMI. MMP-9/TIMP-1, MMP-9/TIMP-2, and MMP-9/TIMP-3 ratios were higher in the PCOS group (p < 0.01), whilst MMP-17/TIMP-1 and MMP-17/TIMP-2 were lower (p = 0.01). MMP-2/TIMP ratios showed no difference between groups. TIMP-2 was positively correlated with CRP (p < 0.01). MMP changes in PCOS are largely driven by BMI, though increased MMP-9 is BMI-independent, suggesting that any deleterious effects of MMP-9 would be potentially exacerbated by a concomitantly increased BMI. The significant increases in the MMP-9/TIMP ratios suggests MMP-9 overactivity in PCOS. Full article

(This article belongs to the Special Issue The Extracellular Matrix in Physiopathology)

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