Positive and negative feedback regulation of the TGF-β1–SMAD4 axis explains two equilibrium states in human skin aging

Summary Skin homeostasis during aging is critical not only for the appearance but also biological defense of the human body. In this study, we identified thrombospondin-1 (THBS1) and fibromodulin (FMOD) as positive and negative regulators, respectively, of the TGF-β1–SMAD4 axis in human skin aging based on in vitro and in vivo omics analyses and mathematical modeling. Transcriptomic and epigenetic analyses of senescent dermal fibroblasts identified TGF-β1 as the key upstream regulator. Bifurcation analysis identified a binary senescent/non-senescent switch, with THBS1 as the main controller. Sensitivity analysis of the TGF-β1 signaling pathway indicated that THBS1 expression was sensitively regulated while FMOD was robustly regulated, suggesting that THBS1 is a controllable factor. Inhibition of SMAD4 complex formation was experimentally validated as a promising manner to control THBS1 production and senescence. This study demonstrates the potential of a data-driven mathematical approach in determining the mechanisms of skin aging. Graphical abstract eTOC Blurb Haga, Iida and Okada revealed that the balance between FMOD and THBS1 determines the two equilibrium states of skin homeostasis and THBS1 is a controllable factor in skin aging Highlights Multi-omics analysis identified TGF-β1–SMAD4 as key regulators in human skin aging THBS1 and FMOD promoted and suppressed factors in skin aging, respectively THBS1 controlled the senescent and non-senescent states of the aging switch SMAD4 is a potential target for inhibiting THBS1 expression and cell senescence