Transcriptomic characterization of the delayed wound healing response in a diabetic skin humanized mice model
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE147890 | GEO | 2021/02/01
REPOSITORIES: GEO
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Project description:This study investigates the effects of environmentally-relevant concentrations of fluoxetine (FLX, commercial name: Prozac) on wound healing. Pollution of water systems with pharmaceutical and care products, including antidepressants such as FLX and other selective serotonin reuptake inhibitors, is a growing environmental concern. Environmentally-relevant FLX concentrations are known to impact physiological functions and behaviour of aquatic animals, however, the effects of exposure on humans are currently unknown. Using a combination of human skin biopsies and keratinocyte cell lines, we show that exposure to environmental FLX enhances wound closure. We show dose-dependent increases in wound closure with FLX concentrations from 125 ng/l. We demonstrate that the mechanisms underlying enhanced wound closure are increased cell proliferation and serotonin signalling. Transcriptomic analysis revealed 350 differentially expressed genes after exposure. Downregulated genes were enriched in pathways related to mitochondrial function and metabolism, while upregulated genes were associated with cell proliferation and tissue morphogenesis. Kinase profiling showed altered phosphorylation of kinases related to the MAPK pathway. Consistent with this, phosphoproteomics analyses identified 235 differentially phosphorylated proteins after exposure, with enriched GO terms related to cell cycle, division, and protein biosynthesis. These findings collectively show that exposure to environmental FLX promotes wound healing through modulation of serotonin signalling, gene expression and protein phosphorylation, leading to enhanced cell proliferation. Our results open the door for further research to investigate the effects of environmental FLX on cell metabolism and proliferation, and clinical applications of FLX in the setting of wound healing. We argue that there is an urgent need to develop models that can inform on the risks, and potential benefits, of environmental pollution with selective serotonin reuptake inhibitors.
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Project description:Skin wound healing is one of the major prevalent medical problems in the worldwide. Wound healing involves multi-process synergy and re-epithelialization is an essential part of wound healing. Histone H3K36 tri-methylase Setd2 has been extensively studied in different biological processes and diseases. However, the function of Setd2 in the wound healing remains unclear. To elucidate the biological role of Setd2 in the skin wound healing, conditional gene targeting was employed to establish epidermis-specific Setd2-deficient mice. We found that Setd2 deficiency resulted in accelerated re-epithelialization during cutaneous wound healing by promoting keratinocytes proliferation and migration. Furthermore, we demonstrated that loss of Setd2 activated the AKT/mTOR pathway, and pharmacological inhibitions of AKT and mTOR with MK2206 and rapamycin delayed wound closure, respectively. In conclusion, our results reveal the essential role of Setd2 in skin wound healing that is Setd2 loss promotes cutaneous wound healing via activation of AKT/mTOR signaling.
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Project description:Skin wound healing is one of the major prevalent medical problems in the worldwide. Wound healing involves multi-process synergy and re-epithelialization is an essential part of wound healing. Histone H3K36 tri-methylase Setd2 has been extensively studied in different biological processes and diseases. However, the function of Setd2 in the wound healing remains unclear. To elucidate the biological role of Setd2 in the skin wound healing, conditional gene targeting was employed to establish epidermis-specific Setd2-deficient mice. We found that Setd2 deficiency resulted in accelerated re-epithelialization during cutaneous wound healing by promoting keratinocytes proliferation and migration. Furthermore, we demonstrated that loss of Setd2 activated the AKT/mTOR pathway, and pharmacological inhibitions of AKT and mTOR with MK2206 and rapamycin delayed wound closure, respectively. In conclusion, our results reveal the essential role of Setd2 in skin wound healing that is Setd2 loss promotes cutaneous wound healing via activation of AKT/mTOR signaling.
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Project description:Mice were wounded and measured for regeneration starting 4 days after wound closure with simultaneous measurement of hair follicle neogenesis and biopsing. At each time point, RNA was collected from one mouse with high number of regenerated follicles and one without regenerated follicles. Whole skin biopsies of wound scars were submitted for Affymetrix Exon arrays. 3 replicates of mice with high number of regenerated follicles, 3 replicates of mice with no regenerated follicles; each pair taken at a different date after wound closure.
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Project description:Targeting senescent cells for therapeutic purposes is gaining momentum across various organ systems. However, concerns about potential off-target effects have been raised. Previous studies have shown that removing senescent cells expressing high levels of p16 (p16high) can hinder processes like wound healing. Here, we identify a distinct senescent cell population during dermal wound healing characterized by high expression level of p21 (p21high) using the p21-Cre mouse model. Using a standard cutaneous injury model, we find that eliminating p21high cells can expedite wound closure, in contrast to the effects of removing p16high cells. Through Xenium, a single cell spatial imaging platform, we show that p21high cells are distinct from p16high cells, with p21high cells mainly comprising fibroblasts, immune cells, keratinocytes, and endothelial cells with a pro-inflammatory profile. Moreover, inhibition of NF-kB signaling specifically from p21high cells partially contributes to the accelerated wound healing rates. These findings highlight the heterogeneity of senescent cells during wound healing responses within the skin and likely in other conditions.
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Project description:The mitogen-activated protein kinase kinase (MEK) kinase 1 (MEKK1), also known as MAP3K1, mediates activin B (ActB) signals required for eyelid epithelium morphogenesis during mouse fetal development. The present study investigates the role of MEKK1 in epithelial wound healing, another activin-regulated biological process. In a skin wound model, injury markedly stimulates MEKK1 expression and activity, which are in turn required for the expression of genes involved in extracellular matrix (ECM) homeostasis. MEKK1 ablation or down-regulation by interfering RNA significantly delays skin wound closure and impairs activation of Jun NH2-terminal kinases, induction of plasminogen activator inhibitor (PAI)-1, and restoration of cell-cell junctions of the wounded epidermis. Conversely, expression of wild-type MEKK1 accelerates reepithelialization of full-thickness skin and corneal debridement wounds by mechanisms involving epithelial cell migration, a cell function that is partially abolished by neutralizing antibodies for PAI-1 and metalloproteinase III. Our data suggest that MEKK1 transmits wound signals, leading to the transcriptional activation of genes involved in ECM homeostasis, epithelial cell migration, and wound reepithelialization.
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