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Defective NCOA4-dependent ferroptosis in senescent fibroblasts retards diabetic wound healing.

ABSTRACT: Cellular senescence describes a state of permanent proliferative arrest in cells. Studies have demonstrated that diabetes promotes the pathological accumulation of senescent cells, which in turn impairs cell movement and proliferation. Historically, senescence has been perceived to be a detrimental consequence of chronic wound healing. However, the underlying mechanism that causes senescent cells to remain in diabetic wounds is yet to be elucidated. Ferroptosis and ferritinophagy observed in diabetes are due to iron metabolism disorders, which are directly associated with the initiation and progression of diabetes. Herein, we reveal that senescent fibroblasts in diabetic wounds are resistant to ferroptosis and that impaired ferritinophagy may be a contributing cause. Further, the expression of NCOA4, a key factor that influences ferritinophagy, is decreased in both diabetic wound tissue and high glucose-induced senescent fibroblasts. Moreover, NCOA4 overexpression could render senescent fibroblasts more vulnerable to ferroptosis. A faster wound healing process was also linked to the induction of ferroptosis. Thus, resistance to ferroptosis impedes the removal of senescent fibroblasts; promoting ferritinophagy could reverse this process, which may have significant implications for the management of diabetic wounds.

SUBMITTER: Wei X

PROVIDER: S-EPMC10147701 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Defective NCOA4-dependent ferroptosis in senescent fibroblasts retards diabetic wound healing.

Wei Xuerong X Liu Mengqian M Zheng Zijun Z Yu Shengxiang S Huang Lei L Ma Jun J Gao Yanbin Y Peng Yujie Y Chen Lianglong L Tan Rongwei R She Zhending Z Yang Lei L

Cell death discovery 20230428 1

Cellular senescence describes a state of permanent proliferative arrest in cells. Studies have demonstrated that diabetes promotes the pathological accumulation of senescent cells, which in turn impairs cell movement and proliferation. Historically, senescence has been perceived to be a detrimental consequence of chronic wound healing. However, the underlying mechanism that causes senescent cells to remain in diabetic wounds is yet to be elucidated. Ferroptosis and ferritinophagy observed in dia ...[more]

PMID: 37117222

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Project description:BackgroundHypoxia-inducible factor 1α is the central regulator of the hypoxia-induced response which results in the up-regulation of angiogenic factors. Its activity is under precise regulation of prolyl-hydroxylase domain 2. We hypothesized that PHD2 silenced fibroblasts would increase the expression of angiogenic factors, which might contribute to the improvement of the diabetic wound healing.Materials and methods50 dB/db mice were employed and randomly assigned into five groups with 10 mice in each: group 1 (untreated cell), group 2 (PHD2 silenced cell), group 3 (L-mimosine treated cells), group 4 (nontargeting siRNA treated cells) and group 5 (sham control). Fibroblasts were cultivated from the dermis of mice in each group and treated with PHD2 targeting siRNA, L-mimosine and non-targeting siRNA respectively. A fraction of the fibroblasts were employed to verify the silencing rate of PHD2 after 48 hours. The autologous fibroblasts (treated and untreated) labeled with adenovirus-GFP were implanted around the wound (Φ6mm), which was created on the dorsum of each mouse. The status of wounds was recorded periodically. Ten days postoperatively, 3 mice from each group were sacrificed and wound tissues were harvested. Molecular biological examinations were performed to evaluate the expressions of cytokines. 28 days postoperatively, the remaining mice were sacrificed. Histological examinations were performed to evaluate the densities of GFP+ cells and capillaries.ResultsThe expression of PHD2 reduced to 12.5%, and the expressions of HIF-1α and VEGFa increased significantly after PHD2 siRNA treatment. With the increasing expressions of HIF-1α and VEGFa, the time to wound closure in group 2 was less than 2 weeks. Increased numbers of GFP+ cells and capillaries were observed in group 2.ConclusionPHD2 siRNA treatment not only increased the expression of HIF1α and VEGFa, but also improved the fibroblast proliferation. These effects might contribute to the improvement of the diabetic wound healing.

Project description:BackgroundPersistent hyperglycaemia in diabetes causes functional abnormalities of human dermal fibroblasts (HDFs), partially leading to delayed skin wound healing. Extracellular vesicles (EVs) containing multiple pro-healing microRNAs (miRNAs) have been shown to exert therapeutic effects on diabetic wound healing. The present study aimed to observe the effects of EVs derived from placental mesenchymal stem cells (P-MSC-EVs) on diabetic wound healing and high glucose (HG)-induced senescent fibroblasts and to explore the underlying mechanisms.MethodsP-MSC-EVs were isolated by differential ultracentrifugation and locally injected into the full-thickness skin wounds of diabetic mice, to observe the beneficial effects on wound healing in vivo by measuring wound closure rates and histological analysis. Next, a series of assays were conducted to evaluate the effects of low (2.28 x 1010 particles/ml) and high (4.56 x 1010 particles/ml) concentrations of P-MSC-EVs on the senescence, proliferation, migration, and apoptosis of HG-induced senescent HDFs in vitro. Then, miRNA microarrays and real-time quantitative PCR (RT-qPCR) were carried out to detect the differentially expressed miRNAs in HDFs after EVs treatment. Specific RNA inhibitors, miRNA mimics, and small interfering RNA (siRNA) were used to evaluate the role of a candidate miRNA and its target genes in P-MSC-EV-induced improvements in the function of HG-induced senescent HDFs.ResultsLocal injection of P-MSC-EVs into diabetic wounds accelerated wound closure and reduced scar widths, with better-organized collagen deposition and decreased p16INK4a expression. In vitro, P-MSC-EVs enhanced the antisenescence, proliferation, migration, and antiapoptotic abilities of HG-induced senescent fibroblasts in a dose-dependent manner. MiR-145-5p was found to be highly enriched in P-MSC-EVs. MiR-145-5p inhibitors effectively attenuated the P-MSC-EV-induced functional improvements of senescent fibroblasts. MiR-145-5p mimics simulated the effects of P-MSC-EVs on functional improvements of fibroblasts by suppressing the expression of cyclin-dependent kinase inhibitor 1A and activating the extracellular signal regulated kinase (Erk)/protein kinase B (Akt) signaling pathway. Furthermore, local application of miR-145-5p agomir mimicked the effects of P-MSC-EVs on wound healing.ConclusionsThese results suggest that P-MSC-EVs accelerate diabetic wound healing by improving the function of senescent fibroblasts through the transfer of miR-145-5p, which targets cyclin-dependent kinase inhibitor 1A to activate the Erk/Akt signaling pathway. P-MSC-EVs are promising therapeutic candidates for diabetic wound treatment.

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Defective NCOA4-dependent ferroptosis in senescent fibroblasts retards diabetic wound healing.

Publications

Defective NCOA4-dependent ferroptosis in senescent fibroblasts retards diabetic wound healing.

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