Coupling fibroblast mechanotransduction signaling to tissue growth in a multiscale model of skin expansion.

Skin growth and remodeling underlies health, disease, and treatments such as tissue expansion (TE). The mechanotransduction pathways in dermal fibroblasts are increasingly well characterized, and tissue-level growth has been described phenomenologically, but coupling between cell-level signaling and tissue-level growth remains poorly understood. We develop a dermal fibroblast signaling network through extensive literature data curation, comprising 151 reactions among 96 nodes. The inputs are mechanical stretch and eight ligands (TGF β , PDGF, FGF, IL1, IL6, TNF α , AngII, ET1); outputs of interest span ECM-enzymes (proMMP1/2/9, MMP1/2/9), ECM proteins (CImRNA, collagen I, fibronectin), and fibroblast activity ( α SMA, proliferation). Implemented as a logic-based ODE system, the network reproduces 82% of the calibration dataset and agrees with independent validation data. Sensitivity analysis reveals a tension-dependent regulation of signaling: at baseline tension, outputs are governed by many boosters (nodes that positively influence downstream targets) and one dominant brake, LATS1/2, whereas at high tension control consolidates and new, tension-specific regulators such as integrin (ITGB1) emerge. Multiple pathway axes converge on a few central regulators, producing pronounced crosstalk, most notably between TGF β and mechanical tension. Finally, linking the collagen outputs to a tissue-level growth formulation yields a bidirectional mechanical-biochemical coupling that reproduces tension-induced skin growth measured in a porcine TE model. This framework establishes a comprehensively calibrated dermal fibroblast signaling network coupled to tissue-level growth, opening opportunities for targeted TE interventions.