Mechanical stiffness promotes skin fibrosis through Piezo1-mediated arginine and proline metabolism.

The increased mechanics of fibrotic skin tissue continuously regulate fibroblast functions such as survival and differentiation. Although all these processes consume metabolites, it is unclear whether and how cells adapt their metabolic activity to increased matrix stiffness. Here, we show that transferring mouse dermal fibroblasts from soft to stiff substrates causes an up-regulation of arginine and proline metabolism. Increased matrix stiffness stimulates the expression and activity of key metabolic enzymes, leading to the synthesis of L-proline, a major source of collagen. In addition, the novel mechanosensitive channel Piezo1 was identified as a key regulator of arginine and proline metabolism in fibroblasts under increased stiffness. Consistently, targeting Piezo1 to dermal fibroblasts in vivo effectively reduces fibrosis and arginine-proline metabolism in mouse skin. Therefore, mechanical stiffness is a critical environmental cue for fibroblast metabolism and skin fibrosis progression.