bims-ecemfi 2025-04-13 papers

Proc Natl Acad Sci U S A. 2025 Apr 15. 122(15): e2417290122

Substrate stress relaxation regulates monolayer fluidity and leader cell formation for collectively migrating epithelia.

Frank Charbonier, Junqin Zhu, Raleigh Slyman, Cole Allan, Ovijit Chaudhuri.

Collective migration of epithelial tissues is a critical feature of developmental morphogenesis and tissue homeostasis. Coherent motion of cell collectives requires large-scale coordination of motion and force generation and is influenced by mechanical properties of the underlying substrate. While tissue viscoelasticity is a ubiquitous feature of biological tissues, its role in mediating collective cell migration is unclear. Here, we have investigated the impact of substrate stress relaxation on the migration of micropatterned epithelial monolayers. Epithelial monolayers exhibit faster collective migration on viscoelastic alginate substrates with slower relaxation timescales, which are more elastic, relative to substrates with faster stress relaxation, which exhibit more viscous loss. Faster migration on slow-relaxing substrates is associated with reduced substrate deformation, greater monolayer fluidity, and enhanced leader cell formation. In contrast, monolayers on fast-relaxing substrates generate substantial substrate deformations and are more jammed within the bulk, with reduced formation of transient lamellipodial protrusions past the monolayer edge leading to slower overall expansion. This work reveals features of collective epithelial dynamics on soft, viscoelastic materials and adds to our understanding of cell-substrate interactions at the tissue scale.

Keywords: cell–substrate interactions; collective cell migration; mechanotransduction; tissue mechanics; viscoelastic substrates

DOI: https://doi.org/10.1073/pnas.2417290122

Adv Healthc Mater. 2025 Apr 10. e2500080

Silk Hydrogel Platform Enable the Design of Aligned and Gradient Cues for Regenerative Medicine.

Liying Xiao, Zhaozhao Ding, Lili Wang, Huaxiang Yang, Qiang Lu.

Tissue regeneration in vivo happens in complex physiological microenvironments that usually involve versatile physical and biological gradients. Introducing controllable gradients to anisotropic biomaterials is critical for the next generation of bioactive biomaterials. Current strategies for introducing gradients to anisotropic biomaterials are highly limited to special cues with inferior controllability. Here, beta-sheet rich silk nanofibers (B-SNFs) are exploited to build aligned hydrogels with controllable gradients, providing a universal approach to fabricating different gradients in anisotropic hydrogels. B-SNFs as carriers are loaded with gradient cues in aqueous solutions, and then the gradients on the aligned hydrogels under the electrical field are stabilized due to their stagnant behaviors in aqueous solutions and directional movement under the electrical field. The anisotropy, gradient strength/type, and gradient interval of the hydrogels are regulated through tuning the B-SNF concentration, the gradients of cues in solution, and the intervals of the compartments, suggesting good controllability. Both biological and physical gradient cues are effectively introduced to the aligned hydrogels and exhibit efficient gradient control of cell behavior. The versatility, controllability, and designability of the hydrogel platform suggest an opportunity to design versatile bioactive gradient materials needed in regenerative medicine.

Keywords: bioactive niche; gradient cues; hydrogel; regenerative medicine; silk

DOI: https://doi.org/10.1002/adhm.202500080

Matter. 2024 Apr 03. 7(4): 1533-1557

Tension in the ranks: Cooperative cell contractions drive force-dependent collagen assembly in human fibroblast culture.

Alexandra A Silverman, Jason D Olszewski, Seyed Mohammad Siadat, Jeffrey W Ruberti.

Currently, there is no mechanistic model that fully explains the initial synthesis and organization of durable animal structure. As a result, our understanding of extracellular matrix (ECM) development and pathologies (e.g., persistent fibrosis) remains limited. Here, we identify and characterize cell-generated mechanical strains that direct the assembly of the ECM. Cell kinematics comprise cooperative retrograde "pulls" that organize and precipitate biopolymer structure along lines of tension. High-resolution optical microscopy revealed five unique classes of retrograde "pulls" that result in the production of filaments. Live-cell confocal imaging confirmed that retrograde pulls can directly cause the formation of fibronectin filaments that then colocalize with collagen aggregates exported from the cell, producing persistent elongated structures aligned with the direction of the tension. The findings suggest a new model for initial durable structure formation in animals. The results have important implications for ECM development and growth and life-threatening pathologies of the ECM, such as fibrosis.

DOI: https://doi.org/10.1016/j.matt.2024.01.023

J Transl Med. 2025 Apr 11. 23(1): 436

Matrix metalloproteinase-driven epithelial-mesenchymal transition: implications in health and disease.

Ghazaleh Khalili-Tanha, Evette S Radisky, Derek C Radisky, Alireza Shoari.

Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells, defined by apical-basal polarity and tight intercellular junctions, acquire migratory and invasive properties characteristic of mesenchymal cells. Under normal conditions, EMT directs essential morphogenetic events in embryogenesis and supports tissue repair. When dysregulated, EMT contributes to pathological processes such as organ fibrosis, chronic inflammation, and cancer progression and metastasis. Matrix metalloproteinases (MMPs)-a family of zinc-dependent proteases that degrade structural components of the extracellular matrix-sit at the nexus of this transition by dismantling basement membranes, activating pro-EMT signaling pathways, and cleaving adhesion molecules. When normally regulated, MMPs promote balanced ECM turnover and support the cyclical remodeling necessary for proper development, wound healing, and tissue homeostasis. When abnormally regulated, MMPs drive excessive ECM turnover, thereby promoting EMT-related pathologies, including tumor progression and fibrotic disease. This review provides an integrated overview of the molecular mechanisms by which MMPs both initiate and sustain EMT under physiological and disease conditions. It discusses how MMPs can potentiate EMT through TGF-β and Wnt/β-catenin signaling, disrupt cell-cell junction proteins, and potentiate the action of hypoxia-inducible factors in the tumor microenvironment. It discusses how these pathologic processes remodel tissues during fibrosis, and fuel cancer cell invasion, metastasis, and resistance to therapy. Finally, the review explores emerging therapeutic strategies that selectively target MMPs and EMT, ranging from CRISPR/Cas-mediated interventions to engineered tissue inhibitors of metalloproteinases (TIMPs), and demonstrates how such approaches may suppress pathological EMT without compromising its indispensable roles in normal biology.

Keywords: Cancer metastasis; Epithelial–mesenchymal transition (EMT); Extracellular matrix (ECM) remodeling; Matrix metalloproteinases (MMPs)

DOI: https://doi.org/10.1186/s12967-025-06447-w