Ahmed Donia W, Tan Matthew L, Liu Yuchen, Gabbard Jackson, Gao Esther, Roy Avinava, Hu Michael M, Midekssa Firaol S, Stevens Miriam, Wuchu Fulei, Nenwani Minal, Xia Jingyi, Abraham Adam, Nagrath Deepak, Han Lin, Zemans Rachel L, Baker Brendon M, Loebel Claudia
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI, USA.
Nat Mater. 2025 Sep 5. doi: 10.1038/s41563-025-02329-0.
Within most tissues, the extracellular microenvironment provides mechanical cues that guide cell fate and function. Changes in the extracellular matrix such as aberrant deposition, densification and increased crosslinking are hallmarks of late-stage fibrotic diseases that often lead to organ dysfunction. Biomaterials have been widely used to mimic the mechanical properties of the fibrotic matrix and study pathophysiologic cell function. However, the initiation of fibrosis has largely been overlooked, due to challenges in recapitulating early stages of disease progression within the native extracellular microenvironment. Here, using visible-light-mediated photochemistry, we induced local crosslinking and stiffening of extracellular matrix proteins within ex vivo mouse and human lung tissue. In ex vivo lung tissue of epithelial cell lineage-traced mice, local matrix crosslinking mimicked early fibrotic lesions that increased alveolar epithelial cell mechanosensing, differentiation, and nascent protein deposition and remodelling. However, the inhibition of cytoskeletal tension, mechanosensitive signalling pathways or integrin engagement reduced epithelial cell spreading and differentiation. Our findings emphasize the role of local extracellular matrix crosslinking and nascent protein deposition in early stage tissue fibrosis and have implications for ex vivo disease modelling and applications to other tissues.
在大多数组织中，细胞外微环境提供引导细胞命运和功能的机械信号。细胞外基质的变化，如异常沉积、致密化和交联增加，是晚期纤维化疾病的标志，这些疾病常常导致器官功能障碍。生物材料已被广泛用于模拟纤维化基质的机械性能并研究病理生理细胞功能。然而，由于在天然细胞外微环境中重现疾病进展早期阶段存在挑战，纤维化的起始在很大程度上被忽视了。在此，我们利用可见光介导的光化学方法，在离体小鼠和人肺组织中诱导细胞外基质蛋白的局部交联和硬化。在上皮细胞谱系追踪小鼠的离体肺组织中，局部基质交联模拟了早期纤维化病变，增加了肺泡上皮细胞的机械传感、分化以及新生蛋白沉积和重塑。然而，细胞骨架张力、机械敏感信号通路或整合素结合的抑制会降低上皮细胞的铺展和分化。我们的研究结果强调了局部细胞外基质交联和新生蛋白沉积在早期组织纤维化中的作用，并对离体疾病建模以及在其他组织中的应用具有启示意义。
