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Ageing-induced cell type-specific transcriptomic changes in the skin are associated with abnormal early healing responses to injury

ABSTRACT: The progression of wound healing is delayed in aged skin. Previous studies have demonstrated that early healing responses are the most impacted upon ageing. However, cellular changes that drive a perturbed wound microenvironment have not been fully defined. To glean a comprehensive understanding of cell-intrinsic changes that are acquired during ageing and may perhaps impact early responses to wounds, we performed single-cell RNA sequencing of 78670 cells from young and aged C57BL6/J wild-type mouse skin and Day 3 wounds. Our data underscore substantial changes in the mean proportional distribution and transcriptomic state of skin resident subpopulations in aged but not young tissues. We found that in comparison to young skin, aged skin was characterised by a global increase in basal inflammation sustained by an altered signalling environment driven by impaired keratinocyte differentiation, loss of fibroblast identity and defective macrophage function. Further, we showed that acquired changes in aged skin resident cells persisted after injury resulting in impaired and exacerbated inflammatory responses.

ORGANISM(S): Mus musculus

PROVIDER: GSE267091 | GEO | 2025/12/03

REPOSITORIES: GEO

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Project description:Ageing-related delays in wound healing are well-documented in both human and animal models. However, the mechanisms underlying this impairment in healing progression are not fully understood. In this study, we characterised ageing-associated changes to the structure and function of the skin in young and aged mice and investigated the cellular differences that impacted the progression of wound healing. Full-thickness wounds created on the dorsum of C57BL/6J young and aged mice were excised on Day 0, Day 3 and Day 7 post-wounding for analysis by immunohistochemistry, flow cytometry, RNA sequencing. Our data revealed that macrophages were significantly reduced in aged wounds in comparison to young. Functional transcriptomic analyses showed that macrophages from aged wounds exhibited significantly reduced expression of cell cycle, DNA replication, and repair pathway genes. Furthermore, we uncovered an elevated pro-inflammatory gene expression program in the aged macrophages linked to poor inflammation resolution and excessive tissue damage observed in aged wounds. Altogether, our work provides insights into how poorly healing aged wounds are phenotypically defined by the presence of macrophages with reduced proliferative capacity and an exacerbated inflammatory response, both of which are pathways that can be targeted to improve healing in the elderly.

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Wound healing in aged skin exhibits systems-level alterations in cellular composition and cell-cell communication

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Metabolic Reprogramming and Reliance in Human Skin Wound Healing

Project description:Impaired skin wound healing is a significant global health issue, especially among the elderly. Wound healing is a well-orchestrated process involving the sequential phases of inflammation, proliferation, and tissue remodeling. Although wound healing is a highly dynamic and energy-requiring process, the role of metabolism remains largely unexplored. By combining transcriptomics and metabolomics of human skin biopsy samples, we mapped the core bioenergetic and metabolic changes in normal acute as well as chronic wounds in elderly subjects. We found upregulation of glycolysis, the tricarboxylic acid cycle, glutaminolysis, and β-oxidation in the later stages of acute wound healing and in chronic wounds. To ascertain the role of these metabolic pathways on wound healing, we targeted each pathway in a wound healing assay as well as in a human skin explant model using metabolic inhibitors and stimulants. Enhancement or inhibition of glycolysis and, to a lesser extent, glutaminolysis had a far greater impact on wound healing than similar manipulations of oxidative phosphorylation and fatty acid β-oxidation. These findings increase the understanding of wound metabolism and identify glycolysis and glutaminolysis as potential targets for therapeutic intervention.

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2011-01-01 | E-GEOD-21648 | biostudies-arrayexpress

RNAseq changes in mouse wound with or without time course treatment by Vemurafenib

Project description:BRAF inhibitors are highly effective therapies for patients with BRAF V600 mutated metastatic melanoma. Patients who receive BRAF inhibitors develop a variety of hyper-proliferative skin conditions, whose pathogenic basis is the paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway in BRAF wild-type cells. Most of these hyper-proliferative skin changes improve when a MEK inhibitor is co-administered, as a MEK inhibitor blocks paradoxical MAPK activation. We tested whether we could take advantage of the mechanistic understanding of the skin hyper-proliferative side effects of BRAF inhibitors to accelerate skin wound healing by inducing paradoxical MAPK activation. Here we show that the BRAF inhibitor vemurafenib accelerates human keratinocyte proliferation and migration by increasing ERK phosphorylation and cell cycle progression. Topical treatment with vemurafenib in two wound-healing models in mice accelerated cutaneous wound healing and improved the tensile strength of healing wounds through paradoxical MAPK activation; addition of a MEK inhibitor reversed the benefit of vemurafenib-accelerated wound healing. The same dosing regimen of topical BRAF inhibitor did not increase the incidence of cutaneous squamous cell carcinomas in mice even after the application of a carcinogen. Therefore, topical BRAF inhibitors may have clinical applications in accelerating the healing of skin wounds. Full depth incisional wound mice tissues with/without Vemurafenib treatment were sent for RNAseq analysis on day 2, 6 and 14

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