Integrins are cellular receptors that bind the extracellular matrix (ECM) and facilitate the transduction of biochemical and biophysical microenvironment cues into cellular responses. Upon engaging the ECM, integrin heterodimers must rapidly strengthen their binding with the ECM, resulting in the assembly of force-resistant and force-sensitive integrin associated complexes (IACs). The IACs constitute an essential apparatus for downstream signaling and fibroblast phenotypes. During wound healing, integrin signaling is essential for fibroblast motility, proliferation, ECM reorganization and, ultimately, restoration of tissue homeostasis. Semaphorin 7A (SEMA7a) has been previously implicated in post-injury inflammation and tissue fibrosis, yet little is known about SEMA7a's role in directing stromal cell, particularly fibroblast, behaviors. We demonstrate that SEMA7a regulates integrin signaling through cis-coupling with active integrin α5β1 on the plasma membrane, enabling rapid integrin adhesion strengthening to fibronectin (Fn) and normal downstream mechanotransduction. This molecular function of SEMA7a potently regulates fibroblast adhesive, cytoskeletal, and migratory phenotype with strong evidence of downstream alterations in chromatin structure resulting in global transcriptomic reprogramming such that loss of SEMA7a expression is sufficient to impair the normal migratory and ECM assembly phenotype of fibroblasts resulting in significantly delayed tissue repair in vivo.

整合素是结合细胞外基质 (ECM) 并促进生化和生物物理微环境线索转导为细胞反应的细胞受体。与 ECM 结合后，整合素异二聚体必须迅速加强与 ECM 的结合，从而组装出抗力和力敏感的整合素相关复合物 (IAC)。IAC 构成下游信号传导和成纤维细胞表型的重要装置。在伤口愈合过程中，整合素信号传导对于成纤维细胞运动、增殖、ECM 重组以及最终恢复组织稳态至关重要。Semaphorin 7A (SEMA7a) 先前被认为与损伤后炎症和组织纤维化有关，但人们对 SEMA7a 在指导基质细胞（特别是成纤维细胞）行为中的作用知之甚少。我们证明SEMA7a通过与质膜上的活性整合素α5β1顺式偶联来调节整合素信号传导，从而能够快速强化整合素对纤连蛋白（Fn）的粘附和正常的下游机械转导。SEMA7a 的这种分子功能有效调节成纤维细胞粘附、细胞骨架和迁移表型，有强有力的证据表明染色质结构的下游改变导致全局转录组重编程，因此 SEMA7a 表达的丧失足以损害成纤维细胞的正常迁移和 ECM 组装表型，从而导致显着延迟体内组织修复。