Defining the role of fibroblasts in skin expansion

Stretch-mediated tissue expansion is commonly used to grow extra skin for reconstructive surgeries. To ensure harmonious growth, the two main skin compartments, the epidermis and the dermis, must both expand in a coordinated manner. Although the epidermal response has been previously described, it remains unclear how fibroblasts, the main supporting cell type, respond to stretching in vivo. Here we map the transcriptional response of the entire skin during stretch-mediated tissue expansion, and we describe the fibroblast response to stretching in vivo. We show an increase in fibroblast volume accompanied by changes in organisation. We demonstrate that stretching forces fibroblasts to exit their quiescent state and restart proliferation. Simultaneously, fibroblasts decrease their collagen content and increase the expression of specific extracellular matrix remodelling factors. By combining data from the in vivo stretching model and an in vitro keratinocyte-fibroblast co-culture system, we demonstrate that changes in fibroblasts promote the self-renewal of the epidermal stem cells, thus coordinating the response of these two compartments during skin expansion. These findings provide valuable insights to guide the design of in vivo stretch-mediated tissue expansion protocols and the production of in vitro skin grafts for clinical application.