Project description:To identify the candidate miRNAs that might compromise wound healing and contribute to the age-associated delay in wound repair, global miRNA profiling was performed in mouse back telogen skin of young (8-week-old) and aged (2-year-old) animals.
Project description:An effective healing response is critical to healthy aging. Thus, the connection of regeneration and aging is needed to understand the complicated age-related healing process. Energy metabolism has been a common hallmark of both studies. In recent years, it become an emerging factor of skin homeostasis. Adenine nucleotide translocase-2 (ANT2) is a known cell proliferation marker and mediator of ATP import into mitochondria for energy homeostasis. Although energy homeostasis and the maintenance of mitochondrial function are critical for wound healing, the role of ANT2 in wound healing has not been elucidated. We found that ANT2 expression decreased during aging in mouse skin as well as during cellular senescence. Interestingly, overexpression of ANT2 in aged mouse skin promoted the healing of full-thickness cutaneous wounds. In addition, upregulation of ANT2 in replicative senescent human diploid dermal fibroblasts (HDFs) induced cell proliferation and migration, which are critical for the wound healing process. Furthermore, overexpression of ANT2 increased ATP production rate by activating the glycolysis pathway and also increased mitophagy, both of which are involved in energy homeostasis. Notably, ANT2-mediated upregulation of HSPA6 in aged HDFs inhibited the expression of pro-inflammatory genes that mediate cellular senescence and mitochondrial damage. This study demonstrates a new physiological role of ANT2 in skin wound healing via regulation of cell proliferation, energy homeostasis, and inflammation. Thus, our study links energy metabolism to skin homeostasis and identifies a genetic factor for improving wound healing with aging model.
Project description:Delayed and often impaired wound healing in the elderly presents major medical, social, and economic challenges. A systematic understanding of the cellular and molecular changes that shape complex cell-cell communications in aged skin wounds is lacking. Here we use single-cell RNA sequencing to define baseline differences across epithelial/fibroblast/immune cell types in young and aged skin during homeostasis and identify major changes in their subset compositions, kinetics, and molecular profiles during wound healing. Our data uncover a more pronounced inflammatory phenotype in aged skin wounds, featuring more neutrophils, a previously unknown inflammatory/glycolytic Arg1Hi macrophage subset, and fewer dendritic cells, compared to young counterparts. Generalizing our computational tool CellChat to compare signaling changes in young vs. aged skin wounds, we find specific alterations in Arg1Hi macrophage-fibroblast signaling interactions and the overall cell-cell communication networks. Finally, our systems-level and experimental analyses uncover dysregulated growth factor, chemokine, and cytokine pathways (e.g., IL-1, Ccl19-Ccr7) in aged skin wounds. Our study exposes numerous cellular and molecular targets for future functional interrogation.
Project description:Acomys exhibits a blunted immune response to wounding, and shares characteristics with fetal wound healing We used mouse microarrays to compare gene expression profiles during wound healing between the African spiny mouse (Acomys) and the house mouse (Mus)
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.
Project description:The full complement of hair follicles is generated during embryogenesis. Normally, no new hair is created after this time. Large full thickness skin excision wounding can result in the generation of new hair in the adult. Placodes can be observed following complete reepithelialization at wound day 14. The events leading to hair neogenesis following wounding remain poorly understood. Late healing events (from wound day 10 to wound day 14) provide a possible window of induction for hair regeneration. We used microarrays to analyse changes in gene expression during late skin healing to provide candidates for factors involved in hair neogenesis following wounding. 6 week old C57Bl/6 mice received large full thickness skin excisions. Healing wound tissue was excised at wound day 10, 12 or 14 and analyzed for gene expression.