SEMA7a primes integrin α5β1 engagement instructing fibroblast mechanotransduction, phenotype and transcriptional programming

•Semaphorin 7a (SEMA7a) is essential for normal mechanotransduction and cell migration of human lung fibroblasts.•SEMA7a surface expression and its integrin cis-binding RGD motif enable rapid adhesion strengthening and focal adhesion maturation of fibroblasts when interacting with fibronectin.•SEMA7a is critical in maintaining a normal signaling balance between αvβ3 and α5β1 integrin during assembly of integrin associated complexes.•Loss of SEMA7a results in global chromosomal restructuring and transcriptional reprogramming suggestive of a critical role of SEMA7a in fibroblast differentiation and phenotype.•SEMA7a−/− mice showed significantly impaired dermal wound healing, likely due to defective fibroblast phenotype.