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bioRxiv · 10.1101/2023.07.18.546970

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

Haga, M.·Iida, K.·Okada, M.
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Abstract

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-{beta}1-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-{beta}1 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-{beta}1 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/546970v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@12b4f29org.highwire.dtl.DTLVardef@5a3e95org.highwire.dtl.DTLVardef@c2daa5org.highwire.dtl.DTLVardef@a09042_HPS_FORMAT_FIGEXP M_FIG C_FIG eTOC BlurbHaga, 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 HighlightsO_LIMulti-omics analysis identified TGF-{beta}1-SMAD4 as key regulators in human skin aging C_LIO_LITHBS1 and FMOD promoted and suppressed factors in skin aging, respectively C_LIO_LITHBS1 controlled the senescent and non-senescent states of the aging switch C_LIO_LISMAD4 is a potential target for inhibiting THBS1 expression and cell senescence C_LI

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Haga, M., Iida, K., Okada, M.. 2023-07-19. Positive and negative feedback regulation of the TGF-β1-SMAD4 axis explains two equilibrium states in human skin aging. https://doi.org/10.1101/2023.07.18.546970

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