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Topical application of an irreversible small molecule inhibitor of Lysyl Oxidases ameliorates skin scarring and fibrosis

ABSTRACT: Next-generation sequencing (NGS) has been performed to investigate the effect of Lysyl oxidase inhibition by PXS-4787A on transcriptome of normal skin derived fibroblasts and keratinocytes. Fibroblasts and keratinocytes of low passage (p2-5) were cultured onto T25 flasks until ~70% confluence was reached. Fibroblasts were treated with or without 10 µM PXS-4787A in complete fibroblast growth media for 48 hours at 37°C. Keratinocytes were treated with 10 µM PXS-4787A with basal keratinocyte medium supplemented with 1.2 mM calcium chloride for 48 hours at 37°C. Cells were then collected using 0.05% trypsin and washed in Phosphate Buffered Saline (PBS). RNA was extracted using the RNeasy Mini kit protocol. Samples were then sent to the Australian Genome Research Facility (AGRF) where 1μg of RNA was submitted for next-generation sequencing. Once raw data returned, bioinformatics analyses were conducted. This study found that the exposure of PXS-4787A only had minor impact on gene expression in both fibroblasts and keratinocytes. In fibroblasts, 3 genes were significantly upregulated and only one gene was significantly downregulated. Besides, There were only two upregulated genes in the whole genome analysis after LOX inhibition in keratinocytes. In conclusion, this study highlights the safety of LOX-inhibition through PXS-4787A on primary human epidermal cells. The results of the transcriptome analysis intimate that PXS-4787A treatment has no adverse effects on the healthy keratinocytes. Taken together, this study suggests that LOX-inhibition has no potential effects on the epidermal differentiation in human skin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE163309 | GEO | 2020/12/17

REPOSITORIES: GEO

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Project description:Hair follicle formation depends on reciprocal epidermal-dermal interactions and occurs during skin development, but not in adult life. This suggests that the properties of dermal fibroblasts change during postnatal development. To examine this, we used a PdgfraEGFP mouse line to isolate GFP-positive fibroblasts from neonatal skin, adult telogen and anagen skin and adult skin in which ectopic hair follicles had been induced (EF skin) by transgenic epidermal activation of beta-catenin. We also isolated epidermal cells from each mouse. The gene expression profile of EF epidermis was most similar to that of anagen epidermis, consistent with activation of beta-catenin signalling. In contrast, adult dermis with ectopic hair follicles more closely resembled neonatal dermis than adult telogen or anagen dermis. In particular, genes associated with mitosis were upregulated and extracellular matrix-associated genes were downregulated in neonatal and EF fibroblasts. We confirmed that sustained epidermal beta-catenin activation stimulated fibroblasts to proliferate to reach the high cell density of neonatal skin. In addition, the extracellular matrix was comprehensively remodelled, with mature collagen being replaced by collagen subtypes normally present only in developing skin. The changes in proliferation and extracellular matrix composition originated from a specific subpopulation of fibroblasts located beneath the sebaceous gland. Our results show that adult dermis is an unexpectedly plastic tissue that can be reprogrammed to acquire the molecular, cellular and structural characteristics of neonatal dermis in response to cues from the overlying epidermis. We have isolated the following populations of cells from mouse back skin by flow cytometry: 1A) GFP+ WT neonatal dermal fibroblasts, 1B) ItgA6+ WT neonatal epidermal keratinocytes, 2A) GFP+ WT telogen dermal fibroblasts, 2B) ItgA6+ WT telogen epidermal keratinocytes, 3A) GFP+ D2 transient activation (anagen) dermal fibroblasts, 3B) ItgA6+ D2 transient activation (anagen) epidermal keratinocytes, 4A) GFP+ D2 sustained activation (ectopic follicles) dermal fibroblasts, 4B) ItgA6+ D2 sustained activation (ectopic follicles) epidermal keratinocytes

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Topical application of an irreversible small molecule inhibitor of Lysyl Oxidases ameliorates skin scarring and fibrosis

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