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RGD-mediated biomimetic dynamic matrix stiffness signaling enable rapid 3D organoid formation

ABSTRACT: Stiffness of extracellular matrix (ECM) is crucial for regulating tissue morphogenesis and cellular behavior. The Arg-Gly-Asp (RGD) motif is a key integrin ligand. However, whether RGD regulates cellular function and tissue remodeling through mechanical stiffness-driven mechanical signaling remains unclear. Here, we develop an easily prepared, ECM-free RGD-functionalized carboxymethylcellulose (CMC) hydrogel. By modulating its mechanical strength, the synergistic effect between RGD-mediated integrin linking and matrix stiffness regulates the formation and expansion of a wide range of tissue-specific organoids through the mechanical transduction pathway of integrin β1/FAK/YAP. Finally, using this method, we develop an acral melanoma organoid model that simulates its development driven by mechanical force and provides a platform for drug screening. These results highlight that RGD-functionalized, stiffness-tunable hydrogel is an excellent biomimetic model for investigating mechanotransduction-driven cell development and disease progression, providing a low-cost strategy for future high-throughput drug screening using organoids.

ORGANISM(S): Homo Sapiens

SUBMITTER: Ling Leng

PROVIDER: PXD076446 | iProX | Wed Apr 01 00:00:00 BST 2026

REPOSITORIES: iProX

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Project description:Vocal fold (VF) fibrosis, often caused by phonosurgery, radiation, or trauma, leads to irreversible voice dysfunction due to excessive ECM deposition and increased tissue stiffness. VF fibrosis, a significant cause of chronic dysphonia, lacks FDA-approved treatments, highlighting the critical need for novel antifibrotic therapeutic. TGF-β1 is a major driver in the pathological transformation of fibroblasts into contractile myofibroblasts in VF fibrosis via SMAD3, YAP1, and integrin signaling pathways. These pathways lead to increased ACTA2 expression, excessive collagen production, and progressive tissue stiffening. Leveraging the principle that local cells respond to tissue-specific signals, our ECM hydrogel derived from decellularized vocal fold lamina propria (VFLP-ECM) reduced ACTA2 expression in TGF-β1 stimulated vocal fold fibroblasts, showcasing antifibrotic potential. In this study, we evaluated the therapeutic potential of VFLP-ECM hydrogel in a rabbit VF injury model—treatment involved VFLP-ECM or bovine type I collagen injections into VFs 7 days after injury, with evaluations at 28 days post-injury. We compared two VFLP-ECM formulations: a manual process (VFLP (man)) and an accelerated automated method (VFLP (au)). VFLP (man) showed more modulated fibrosis-associated gene expressions when compared to VFLP (au) and collagen. Proteomic analysis revealed that VFLP (man) preserves a broader array of bioactive proteins, such as vitronectin, crucial in TGF-β1 signaling and ECM remodeling. The transcriptomic analysis uncovered a downregulation of key fibrotic markers and potential inhibition of regulators such as SMAD3, YAP1, and MRTFA, alongside the upregulation of SMAD7, an inhibitor of TGF-β signaling. Notably, treatment with VFLP (man) resulted in vocal folds with similar stiffness as uninjured controls, whereas tissues treated with collagen or VFLP (au) remained stiffer, indicating incomplete mechanical recovery. These data provide the first in vivo evidence that VFLP-ECM hydrogel—mainly when produced via manual decellularization—attenuates fibrosis by disrupting biochemical and biomechanical drivers of myofibroblast activation.

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RGD-mediated biomimetic dynamic matrix stiffness signaling enable rapid 3D organoid formation

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