Matrix Stiffness Modulates Fibroblast Paracrine Signaling to Enhance Autophagy in Keratinocytes: Implications for Wound Healing

Wound healing is profoundly influenced by the mechanical properties of the extracellular matrix; however, the mechanisms by which these mechanical cues coordinate intercellular communication remain incompletely understood. Focusing on skin wound healing, we investigated whether the stiffness of the matrix sensed by dermal fibroblasts (HSF) could modulate the autophagic activity of keratinocytes (HaCaT) via paracrine signaling. Using a three-dimensional coculture model, we show that a high-stiffness matrix activates mechanosignaling in fibroblasts, which subsequently enhances autophagy in keratinocytes through a paracrine mechanism. This study delineates a 'matrix stiffness-fibroblast mechanosensing-keratinocyte autophagy' signaling axis and, through RNA-seq, links this mechanical dialogue to pathways associated with cellular stress responses. These in vitro findings establish a novel framework for mechano-driven intercellular communication, suggesting that modulating fibroblast mechanosignaling could inform future strategies for influencing tissue repair.