Fig. 4. Mechanical stress drives profibrotic fibroblast heterogeneity; subsequent inhibition of mechanotransduction reduces heterogeneity and triggers AKT-dependent EGR1 and MFGE8 expression.

a Adult human dermal fibroblasts were isolated from tissue collected from three patients at different anatomical locations: the breast skin from a mastectomy sample, the abdomen skin from an abdominoplasty sample, and the thigh skin from a thighplasty sample. Freshly isolated fibroblasts were seeded into 3D collagen scaffolds and subjected to either no strain (NS, gray), strain (S, blue), or strain +10 μM FAKI (S + FAKI, red) and then submitted for 10× genomics. b UMAP embeddings of cellular transcription profiles for the three patients were combined into a final embedding. c Unsupervised clustering of fibroblast transcriptional signatures revealed a total of 9 distinct clusters of human dermal fibroblasts (clusters 0–8). d Heatmap of the top five differentially expressed genes in all clusters. e Violin plots of group-defining differentially expressed genes. f Gene expression of group-defining genes projected onto UMAP embedding. g Over-representation analysis (ORA) of key pathways that differentiate the groups projected onto UMAP embedding.