PT  - JOURNAL ARTICLE
AU  - Jun Muto
AU  - Shinji Fukuda
AU  - Kenji Watanabe
AU  - Xiuju Dai
AU  - Teruko Tsuda
AU  - Takeshi Kiyoi
AU  - Hideki Mori
AU  - Ken Shiraishi
AU  - Masamoto Murakami
AU  - Shigeki Higashiyama
AU  - Yoichi Mizukami
AU  - Koji Sayama
TI  - Highly concentrated trehalose induces transient senescence-associated secretory phenotype in fibroblasts via CDKN1A/p21
AID  - 10.1101/2021.10.06.463325
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.10.06.463325
4099  - http://biorxiv.org/content/early/2021/10/06/2021.10.06.463325.short
4100  - http://biorxiv.org/content/early/2021/10/06/2021.10.06.463325.full
AB  - Trehalose is the nonreducing disaccharide of glucose, evolutionarily conserved in invertebrates, but does not exist in vertebrates. The living skin equivalent (LSE) is an organotypic coculture containing keratinocytes cultivated on fibroblast-populated dermal substitutes. We demonstrated that human primary fibroblasts treated with highly concentrated trehalose promote significantly extensive spread of the epidermal layer of LSE without any deleterious effects. The RNA-seq analysis data and Ingenuity pathway analysis of the differentially expressed genes of trehalose-treated 2D and 3D fibroblasts at early time points revealed the involvement of the CDKN1A pathway, which is necessary for the marked upregulation of growth factors including DPT. By contrast, the mRNA-seq data of LSEs 2-weeks after air exposure indicated that gene expression profiles are similar for untreated and trehalose-treated cells in both keratinocytes and fibroblasts. The trehalose-treated fibroblasts were positive for senescence-associated β-galactosidase with the significantly downregulated expressions of LMNB1. Finally, we demonstrated that transplantation of the dermal substitute with trehalose-treated fibroblasts accelerated wound closure and increased capillary formation significantly in the experimental mouse wounds in vivo. These data indicate that high-concentration trehalose can induce the beneficial senescence-associated secretory phenotype in fibroblasts via CDKN1A/p21, which may be therapeutically useful for optimal wound repair.Competing Interest StatementThe authors have declared no competing interest.