Editorial: Extracellular matrix modifications in development and disease

Karin Pfisterer ^1* Michael Mildner ¹ Maddy Parsons ²

• ¹ Department of Dermatology, Medical University of Vienna, Vienna, Austria
• ² Randall Centre for Cell and Molecular Biophysics, King’s College London, London, United Kingdom

The composiDon, structure, and mechanical properDes of the ECM in the contexts of development and disease has received increasing aSenDon over recent years. This has driven the creaDon of new probes, in vitro and in vivo models, high-resoluDon and in situ imaging methods, bioanalyDcal techniques, computaDonal tools, and in silico modeling. Such approaches are complemented by single cell and spaDal 'omics technology to further profile transcripDonal, proteome and metabolic cell 'states' that associate with specific ECM phenotypes. These innovaDons have greatly advanced our understanding of the biological processes and mechanisms involved in ECM deposiDon, crosslinking, organizaDon, and turnover in health and disease. Gaining a deeper understanding of dynamic funcDonal interplay between cells and surrounding ECM is a pressing research challenge that demands mulDdisciplinary approaches to unravel and facilitate the development of new therapies. This Research Topic brings together a mulDdisciplinary collecDon of studies focused on advancing our understanding of the diverse roles of the ECM in health and disease. The topics covered include current mathemaDcal models to invesDgate ECM-cell interacDons (Crossley, Johnson, Tsingos et al., Keijzer et al.), the role of ECM modificaDons in various diseases (Jahin and Phillips et al., Direder et al., Guerrero-Barberà et al., and Töpfer and Holz) and in ageing (Ulldemolins et al.).Crossley, Johnson, Tsingos et al. provide an overview of structural components of the ECM, briefly describe its characterisDcs and funcDon before deep-diving into a comprehensive descripDon of currently available methods to model ECM dynamics mathemaDcally. The authors compare two main approaches, the conDnuum model, describing Dssue components as a whole using ordinary or parDal differenDal equaDons, and the discrete agent-based model, in which Dssue components can be simulated individually, including la[ce-based and -free approaches and the Cellular PoSs model. The concepts of hybrid models incorporaDng mulDple approaches and mechanical models are discussed before addressing advantages and limitaDons in regard to applicability of current mathemaDcal models to invesDgate Dssue mechanics, cell-matrix interacDons and cell migraDon in silico.developed a novel hybrid model that integrates a Cellular PoSs model to describe shape changes in individual cells, a molecular dynamics model to simulate the dynamics of fibrous ECM networks under cell-generated forces, and an ordinary differenDal equaDon model to describe the dynamics of mechanosensiDve focal adhesions. This computaDonal approach captures both the ECM's influence on cell morphology and orientaDon and the effects of cell contracDons on the ECM structure. The authors incorporated focal adhesion turnover and stability in response to mechanical tension due to cells pulling on the ECM or structural and physical ECM properDes such as fiber crosslinking, alignment, deformaDon, and sDffness. Thus, this hybrid model represents a powerful predicDve tool for in silico invesDgaDons of cell-ECM interacDons and reciprocal force generaDon.Jahin and Phillips et al. invesDgate the role of ECM sDffening in breast cancer spheroid behavior. Combining biomechanically tuned collagen I matrices and advanced 3D imaging, the authors demonstrate that two different breast cancer cell lines show increased YAP and ERK1/2 acDvity in response to increased matrix sDffness. AcDvaDon of both regulators is higher in cells contacDng the ECM at the periphery of spheroids compared to those in the center of the cell mass. Further analysis revealed the a2b1 collagen-binding integrins as key mechanosensiDve receptors in the transmission of sDffer ECM to signaling responses. Contrary to some previous reports however, they demonstrate that this increased sDffnessdependent signaling correlates with lower proliferaDon, lower ECM alignment and reduced invasive potenDal of cells from the spheroid. These findings support the noDon that sDffer ECM, seen in several cancer types, is sufficient to support pro-tumorigenic signaling but that funcDonal consequences of this require contribuDons from addiDonal cell types within the tumor microenvironment.mechanisms underlying idiopathic subglo[c stenosis (ISGS), a rare fibroDc disorder of the upper trachea, uDlizing single-cell RNA sequencing. Their analysis idenDfied fibroblasts and Schwann cells, glial cells of the peripheral nervous system, exhibiDng a disDnct profibroDc phenotype. Furthermore, the study revealed a marked increase in plasma cell populaDons in ISGS. These findings provide novel insights into the pathogenesis of ISGS, potenDally advancing the development of innovaDve diagnosDc and therapeuDc strategies.Guerrero-Barberà et al. comprehensively overview of the role of the abundant ECM protein fibronecDn in cancer progression. Spanning from transcripDonal regulaDon and biosynthesis to cell binding, scaffolding and tumorigenic properDes, the authors highlight criDcal funcDons for this molecule across different regions in the tumor microenvironment. They further explore the potenDal for domain-specific therapeuDc targeDng of fibronecDn in future, both directly and in conjuncDon with integrin antagonists or immunotherapy.Töpfer and Holz provide a concise overview of nidogen, a mulDfuncDonal glycoprotein, highlighDng its role in basement membrane integrity, morphogenesis, and neuronal plasDcity. This review emphasizes nidogen's criDcal funcDon as a linking molecule within the extracellular matrix, effecDvely connecDng various components. AddiDonally, the authors explore the specific roles of nidogen in cell adhesion, migraDon, and signaling.Ulldemolins et al. invesDgated how aging affects the mechanical properDes of lung Dssue using a mouse model. They measured age-related changes in ECM composiDon and biomechanical properDes in decellularized lungs of young and aged mice. Comparing sDffness, viscosity, and adhesion forces in non-inflated and inflated lungs via atomic force microscopy, they found reduced sDffness in aged non-inflated lungs but increased sDffness at funcDonal inflated volumes. Unlike prior studies focusing on non-inflated lungs, this work provides novel insights into lung mechanics under physiological stretch condiDons.All authors wrote, edited and approved this work.