Quantification of Stretch-Induced Stimuli Altering the Mechanome of Dermal Fibroblasts

Deformation is a key determinant of skin pathophysiology, as seen in skin growth during pregnancy and tissue expansion and in pathological processes such as excessive scarring in wounds under tension. However, the mechanisms underlying dermal cell response to deformation are poorly understood, especially when skin elongation alters the biophysical cell environment, that is, the dermal mechanome. In this study, we show that stretch exposes dermal cells to a variety of biophysical stimuli, which can affect cell signaling and gene expression. On the basis of multiaxial, time-dependent mechanical tests on human dermis, we quantified stretch-induced variations of the interstitial fluid osmolarity (10 mOsm/l), hydrostatic pressure (20 kPa), velocity (20 μm/s), and electric field (3 mV/mm). Calcium imaging of human dermal fibroblasts cultured in 2 dimensions and exposed to such biophysical stimuli showed that cells sense variations in hydrostatic pressure, flow velocity, and electric field. The latter 2 stimuli also modified protein kinase B and YAP activation and influenced the expression of genes associated with remodeling of the extracellular matrix (collagens, MMP1, and ANKRD1). Our findings demonstrate that skin stretch induces a wide range of secondary stimuli, which should be considered when studying mechanotransduction and identifying targets of mechanotherapy in the context of growth, tissue remodeling, and fibrosis.