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Highly concentrated trehalose induces prohealing senescence-like state in fibroblasts via CDKN1A/p21

ABSTRACT: Trehalose is the nonreducing disaccharide of glucose, evolutionarily conserved in invertebrates. 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 of trehalose-treated 2D and 3D fibroblasts at early time points revealed the involvement of the CDKN1A pathway, the knockdown of which significantly suppressed the upregulation of DPT, ANGPT2, VEGFA, EREG, and FGF2. The trehalose-treated fibroblasts were positive for senescence-associated β-galactosidase. Finally, transplantation of the dermal substitute with trehalose-treated fibroblasts accelerated wound closure and increased capillary formation significantly in the experimental mouse wounds in vivo, which was canceled by the CDKN1A knockdown. These data indicate that high-concentration trehalose can induce the senescence-like state in fibroblasts via CDKN1A/p21, which may be therapeutically useful for optimal wound repair.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184892 | GEO | 2023/01/10

REPOSITORIES: GEO

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Highly concentrated trehalose induces prohealing senescence-like state in fibroblasts via CDKN1A/p21

Project description:Highly concentrated trehalose induces prohealing senescence-like state in fibroblasts via CDKN1A/p21

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Highly concentrated trehalose prevents IL-4/IL-13-induced skin barrier impairment by suppressing IL-33 expression and increasing Nrf2 activation in epidermal keartinocytes

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Genome-wide analysis of trehalose-responsive gene expression in control or JNCL human fibroblasts.

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Eicosanoid profiles of dermal fibroblasts (part-II)

Project description:The sphingolipid, ceramide-1-phosphate (C1P), directly binds and activates Group IVA cytosolic phospholipase A2 (cPLA2) to generate eicosanoids. Due to the role of eicosanoids in wound healing, we choose to use our novel genetic mouse model expressing cPLA2 with an ablated C1P interaction site (KI) to examine the cPLA2/C1P interaction in wound healing. Wound closure rate was not affected, but wound maturation was enhanced by loss of the C1P/cPLA2α interaction based on the following findings. Wounds in KI mice displayed: i) increased infiltration of dermal fibroblasts into the wound environment; ii) increased wound tensile strength; and iii) higher Type I/Type III collagen ratios. These findings were recapitulated in vitro as primary dermal fibroblasts (pDFs) from KI mice showed significantly increased collagen deposition and migration velocity compared to WT and KO pDFs. Additionally, the KI showed an altered eicosanoid profile of reduced pro-inflammatory prostaglandins (PGE2) and increased levels of specific HETE species (5-HETE). Elevated 5-HETE levels promoted increased dermal fibroblast migration and collagen deposition. This “gain of function” role for the mutant cPLA2 was also linked to differential cellular localization of cPLA2α and 5-HETE biosynthetic factors. These studies demonstrate regulation of key biological mechanisms by a defined protein:lipid interaction in vivo and provide new insights into cPLA2 function.

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Eicosanoid profiles of dermal fibroblasts (part-I)

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A global transcriptome analysis of human dermal fibroblasts upon knockdown or overexpression of the circular RNAs circGLIS3 (circBase ID: hsa_circ_0002874)

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Effects of mycophenolic acid on human fibroblast proliferation, migration and adhesion in vitro and in vivo

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