Ahmed Donia W, Tan Matthew L, Gabbard Jackson, Liu Yuchen, Hu Michael M, Stevens Miriam, Midekssa Firaol S, Han Lin, Zemans Rachel L, Baker Brendon M, Loebel Claudia
Department of Biomedical Engineering University of Michigan.
Department of Materials Science and Engineering University of Michigan.
bioRxiv. 2024 Aug 10:2024.08.10.607417. doi: 10.1101/2024.08.10.607417.
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 cell function. However, the initiation of fibrosis has largely been overlooked, due to the challenges in recapitulating early fibrotic lesions within the native extracellular microenvironment. Using visible light mediated photochemistry, we induced local crosslinking and stiffening of extracellular matrix proteins within murine and human tissue. In lung tissue of epithelial cell lineage-traced mice, local matrix crosslinking mimicked early fibrotic lesions that increased alveolar epithelial cell spreading, differentiation and extracellular matrix remodeling. However, inhibition of cytoskeletal tension or integrin engagement reduced epithelial cell spreading and differentiation, resulting in alveolar epithelial cell dedifferentiation and reduced extracellular matrix deposition. Our findings emphasize the role of local extracellular matrix crosslinking and remodeling in early-stage tissue fibrosis and have implications for disease modeling and applications to other tissues.
在大多数组织中，细胞外微环境提供指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细胞功能。然而，由于在天然细胞外微环境中重现早期纤维化病变存在挑战，纤维化的起始在很大程度上被忽视了。利用可见光介导的光化学，我们在小鼠和人类组织内诱导了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铺展、分化和细胞外基质重塑。然而，细胞骨架张力或整合素结合的抑制减少了上皮细胞的铺展和分化，导致肺泡上皮细胞去分化并减少细胞外基质沉积。我们的研究结果强调了局部细胞外基质交联和重塑在早期组织纤维化中的作用，并对疾病建模以及在其他组织中的应用具有启示意义。
