GCN5 participates in KLF4-VEGFA feedback to promote endometrial angiogenesis

Cao, Can; Zhou, Yanmin; Ma, Yucong; Du, Shouying; Liu, Fan; Niu, Ruobing; Zhang, Yingmei; He, Ming

doi:10.1016/j.isci.2022.104509

Cited by 12 publications

(6 citation statements)

References 54 publications

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“…demonstrated that VEGFA could form a positive feedback loop with KLF4 to promote endometrial angiogenesis of human endometrial microvascular endothelial cells. They not only confirmed the positive transcriptional activation of VEGFA by KLF4 but also confirmed that VEGFA could, in turn, epigenetically regulate the transcriptional activity of KLF4 [ 66 ]. In contrast, Boriushkin et al .…”

Section: Discussionmentioning

confidence: 70%

Extracellular vesicles from 3D cultured dermal papilla cells improve wound healing via Krüppel-like factor 4/vascular endothelial growth factor A -driven angiogenesis

Wang,

Shen,

Sun

et al. 2023

Burns &Amp; Trauma

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Background Non-healing wounds are an intractable problem of major clinical relevance. Evidence has shown that dermal papilla cells (DPCs) may regulate the wound-healing process by secreting extracellular vesicles (EVs). However, low isolation efficiency and restricted cell viability hinder the applications of DPC-EVs in wound healing. In this study, we aimed to develop novel 3D-DPC spheroids (tdDPCs) based on self-feeder 3D culture and to evaluate the roles of tdDPC-EVs in stimulating angiogenesis and skin wound healing. Methods To address the current limitations of DPC-EVs, we previously developed a self-feeder 3D culture method to construct tdDPCs. DPCs and tdDPCs were identified using immunofluorescence staining and flow cytometry. Subsequently, we extracted EVs from the cells and compared the effects of DPC-EVs and tdDPC-EVs on human umbilical vein endothelial cells (HUVECs) in vitro using immunofluorescence staining, a scratch-wound assay and a Transwell assay. We simultaneously established a murine model of full-thickness skin injury and evaluated the effects of DPC-EVs and tdDPC-EVs on wound-healing efficiency in vivo using laser Doppler, as well as hematoxylin and eosin, Masson, CD31 and α-SMA staining. To elucidate the underlying mechanism, we conducted RNA sequencing (RNA-seq) of tdDPC-EV- and phosphate-buffered saline-treated HUVECs. To validate the RNA-seq data, we constructed knockdown and overexpression vectors of Krüppel-like factor 4 (KLF4). Western blotting, a scratch-wound assay, a Transwell assay and a tubule-formation test were performed to detect the protein expression, cell migration and lumen-formation ability of KLF4 and vascular endothelial growth factor A (VEGFA) in HUVECs incubated with tdDPC-EVs after KLF4 knockdown or overexpression. Dual-luciferase reporter gene assays were conducted to verify the activation effect of KLF4 on VEGFA. Results We successfully cultured tdDPCs and extracted EVs from DPCs and tdDPCs. The tdDPC-EVs significantly promoted the proliferation, lumen formation and migration of HUVECs. Unlike DPC-EVs, tdDPC-EVs exhibited significant advantages in terms of promoting angiogenesis, accelerating wound healing and enhancing wound-healing efficiency both in vitro and in vivo. Bioinformatics analysis and further functional experiments verified that the tdDPC-EV-regulated KLF4/VEGFA axis is pivotal in accelerating wound healing. Conclusions 3D cultivation can be utilized as an innovative optimization strategy to effectively develop DPC-derived EVs for the treatment of skin wounds. tdDPC-EVs significantly enhance wound healing via KLF4/VEGFA-driven angiogenesis.

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Section: Discussionmentioning

confidence: 70%

Extracellular vesicles from 3D cultured dermal papilla cells improve wound healing via Krüppel-like factor 4/vascular endothelial growth factor A -driven angiogenesis

Wang,

Shen,

Sun

et al. 2023

Burns &Amp; Trauma

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“…We selected 16 genes for PCR validation, and the results were consistent with the RNA-seq. Among the 16 genes validated through RT-qPCR, TWIST2, VEGFA, and other genes have been identified in previous studies as being associated with endometrial receptivity ( Cao et al 2022 ). We focus on TWIST2, a positive regulator of EMT, which exhibited a significant decrease in expression ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Loss of KLF15 impairs endometrial receptivity by inhibiting EMT in endometriosis

Huang,

Wang,

et al. 2024

Journal of Endocrinology

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The impaired endometrial receptivity is a major factor contributing to infertility in patients with endometriosis (EM), but the underlying mechanism remains unclear. Our study aimed to investigate the role of Kruppel-like factor 15 (KLF15) in endometrial receptivity and its regulation in EM. We observed a significant decrease in KLF15 expression in the mid-secretory epithelial endometrial cells of EM patients compared to normal females without EM. To confirm the role of KLF15 in endometrial receptivity, we found a significantly reduced KLF15 expression and a significant decrease of embryo implantations number in the rat model via uterine horn infection with siRNA. This highlighted importance of KLF15 as a regulator receptivity. Furthermore, through ChIP-qPCR, we discovered that progesterone receptor (PR) directly binds to KLF15 promoter regions, indicating that progesterone resistance may mediate the decrease in KLF15 expression in EM patients. Additionally, we found that the mid-secretory endometrium of EM patients exhibited impaired epithelial-mesenchymal transition (EMT). Knockdown of KLF15 upregulated E-cadherin and downregulated Vimentin expression, leading to inhibited invasiveness and migration of Ishikawa cells. Overexpression KLF15 promotes EMT, invasiveness, and migration ability, and increased attachment rate of JAR cells to Ishikawa cells. Through RNA-seq analysis, we identified TWIST2 as a downstream gene of KLF15. We confirmed that KLF15 directly binds to the promoter region of TWIST2 via ChIP-qPCR, promoting epithelial cells EMT during the establishment of endometrial receptivity. Our study reveals the involvement of KLF15 in the regulation of endometrial receptivity and its downstream effects on EMT. These findings provide valuable insights into potential therapeutic approaches for treating non-receptive endometrium in patients with EM.

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“…How TNF‐ α inhibits mitophagy is an important issue of concern. Cytokines can regulate protein succinylation, [ 29 ] which reportedly regulates mitophagy and the cell cycle. [ 11 , 30 ] Our study showed that TNF‐ α inhibited mitophagy and promoted OXPHOS by increasing the protein succinylation levels in BMMSC.…”

Section: Discussionmentioning

confidence: 99%

TNF‐α‐Induced KAT2A Impedes BMMSC Quiescence by Mediating Succinylation of the Mitophagy‐Related Protein VCP

Su,

Li,

Lin

et al. 2023

Advanced Science

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Regular quiescence and activation are important for the function of bone marrow mesenchymal stem cells (BMMSC), multipotent stem cells that are widely used in the clinic due to their capabilities in tissue repair and inflammatory disease treatment. TNF‐α is previously reported to regulate BMMSC functions, including multilineage differentiation and immunoregulation. The present study demonstrates that TNF‐α impedes quiescence and promotes the activation of BMMSC in vitro and in vivo. Mechanistically, the TNF‐α‐induced expression of KAT2A promotes the succinylation of VCP at K658, which inhibits the interaction between VCP and MFN1 and thus inhibits mitophagy. Furthermore, activated BMMSC exhibits stronger fracture repair and immunoregulation functions in vivo. This study contributes to a better understanding of the mechanisms of BMMSC quiescence and activation and to improving the effectiveness of BMMSC in clinical applications.

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GCN5 participates in KLF4-VEGFA feedback to promote endometrial angiogenesis

Cited by 12 publications

References 54 publications

Extracellular vesicles from 3D cultured dermal papilla cells improve wound healing via Krüppel-like factor 4/vascular endothelial growth factor A -driven angiogenesis

Extracellular vesicles from 3D cultured dermal papilla cells improve wound healing via Krüppel-like factor 4/vascular endothelial growth factor A -driven angiogenesis

Loss of KLF15 impairs endometrial receptivity by inhibiting EMT in endometriosis

TNF‐α‐Induced KAT2A Impedes BMMSC Quiescence by Mediating Succinylation of the Mitophagy‐Related Protein VCP

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