Plasma endothelial cells-derived extracellular vesicles promote wound healing in diabetes through YAP and the PI3K/Akt/mTOR pathway

Wei, Feng; Wang, Aixue; Wang, Qing; Han, Wenrui; Rong, Rong; Wang, Lijuan; Liu, Sijia; Zhang, Yimeng; Dong, Chao; Li, Yanling

doi:10.18632/aging.103366

Cited by 71 publications

(50 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In previous studies, it was reported that YAP1 activity closely correlates with the AKT signaling activation in fibrotic disease ( 29 ), wound healing ( 30 ), etc. Therefore, we evaluated the role of the AKT pathway in YAP1-related EMT by co-treatment of the cells with MK2206, an AKT phosphorylation inhibitor.…”

Section: Resultsmentioning

confidence: 99%

Yap1-2 Isoform Is the Primary Mediator in TGF-β1 Induced EMT in Pancreatic Cancer

et al. 2021

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive human malignancy and intrinsically resistant to conventional therapies. YAP1, as a key downstream effector of the Hippo pathway, plays an important role in tumorigenesis including PDAC. Alternative mRNA splicing of YAP1 results in at least 8 protein isoforms, which are divided into two subgroups (YAP1-1 and YAP1-2) based on the presence of either a single or double WW domains. We investigated the functions and regulatory mechanisms of YAP1-1 and YAP1-2 in PDAC cells induced by TGF-β to undergo epithelial-to-mesenchymal transition (EMT). CRISPR-Cas9 and shRNA were used to silence YAP1 expression in pancreatic cancer cells. Re-constituted lentivirus mediated overexpression of each single YAP1 isoform was generated in the parental knockout L3.6 cells. EMT was induced by treatment with TGF-β, EGF and bFGF in parental and the constructed stable cell lines. Western blot and qPCR were used to detect the expression of EMT markers. Scratch wound healing and transwell assays were used to detect cell migration. The stability and subcellular localization of YAP1 proteins were determined by Western blot analysis, immunofluorescence, as well as ubiquitination assays. We showed that TGF-β, EGF and bFGF all significantly promoted EMT in PDAC cells, which was inhibited by knockdown of YAP1 expression. Interestingly, YAP1-1 stable cells exhibited a stronger migratory ability than YAP1-2 cells under normal culture condition. However, upon TGF-β treatment, L3.6-YAP1-2 cells exhibited a stronger migratory ability than L3.6-YAP1-1 cells. Mechanistically, TGF-β treatment preferentially stabilizes YAP1-2 and enhances its nuclear localization. Furthermore, TGF-β-induced EMT and YAP1-2 activity were both blocked by inhibition of AKT signaling. Our results showed that both YAP1-1 and YAP1-2 isoforms are important mediators in the EMT process of pancreatic cancer. However, YAP1-2 is more important in mediating TGF-β-induced EMT, which requires AKT signaling.

show abstract

Section: Resultsmentioning

confidence: 99%

Yap1-2 Isoform Is the Primary Mediator in TGF-β1 Induced EMT in Pancreatic Cancer

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Additionally, in fibroblasts and epidermal keratinocyte-like cells (HaCaT), they promote nuclear translocation of transcriptional regulator Yes-associated protein (YAP) and subsequently, activation of its downstream effector—connective tissue growth factor (CTGF). This regulatory axis is known to participate in collagen deposition, fibroblast proliferation, and differentiation to myofibroblasts, which are critical in the remodeling phase of wound healing [ 125 , 126 ].…”

Section: The Role Of Extracellular Vesicles In Natural Wound Repairmentioning

confidence: 99%

“… miR-221-3p [ 120 ] Macrophages (RAW 264.7) Mouse endothelial cell line SVEC4-10EHR1; In vivo healthy mouse model ↑ Proliferation, migration, tube formation In vivo: ↑ Angiogenesis VEGF, Wnt3a, miR-130a, miR-126, miR-210. [ 122 ] Diabetic HUVECs In vivo diabetic rat model ↑Angiogenesis, cell migration, proliferation via ↓ IL-6 and TNF-α production; In vivo: ↓ IL-6, TNF-α; ↑ p-Akt, ↓MMP-9; ↑collagen deposition Activated Akt/VEGF [ 121 ] Murine mature osteoblasts Brain-derived endothelial cell line (bEnd.3) ↑ Proliferation, migration, tube formation; ↑ p-VEGFR2, pERK1/2 expression, MMP-2 MMP-2 Activated:VEGF/ERK1/2 [ 123 ] Saliva HUVECs In vivo healthy mice ↑ Proliferation, migration, tube formation; ↓SMAD-6; ↑BMP2; In vivo: ↑ wound healing UBE2O mRNA [ 124 ] Plasma ECs Diabetic skin fibroblasts; HaCaT; In vivo diabetic mouse model ↑Proliferation, migration; ↓ Senescence markers; ↑ YAP dephosphorylation and nuclear translocation In vivo: ↑ wound healing, ↓fibroblast senescence Activated PI3K/Akt/mTOR [ 125 ] HaCaT; HEKa; NHEK Human dermal fibroblasts ↑ TGFBRII , CCN2 , FGF2; laminin-111 , collage...…”

Section: Table A1mentioning

confidence: 99%

Extracellular Vesicles in Skin Wound Healing

et al. 2021

View full text Add to dashboard Cite

Each year, millions of individuals suffer from a non-healing wound, abnormal scarring, or injuries accompanied by an infection. For these cases, scientists are searching for new therapeutic interventions, from which one of the most promising is the use of extracellular vesicles (EVs). Naturally, EV-based signaling takes part in all four wound healing phases: hemostasis, inflammation, proliferation, and remodeling. Such an extensive involvement of EVs suggests exploiting their action to modulate the impaired healing phase. Furthermore, next to their natural wound healing capacity, EVs can be engineered for better defined pharmaceutical purposes, such as carrying specific cargo or targeting specific destinations by labelling them with certain surface proteins. This review aims to promote scientific awareness in basic and translational research of EVs by summarizing the current knowledge about their natural role in each stage of skin repair and the most recent findings in application areas, such as wound healing, skin regeneration, and treatment of dermal diseases, including the stem cell-derived, plant-derived, and engineered EVs.

show abstract

“…It is generally known that IL-10 is an anti-in ammatory cytokine, while IL-6 and TNF-α are pro-in ammatory cytokines. IL-10 appears to in uence the wound-healing environment by decreasing the expression of pro-in ammatory/pro brotic mediators, promoting angiogenesis [38,39]. During wound healing, IL-6 affects brogenesis, angiogenesis, re-epithelialization and granulation tissue formation [40,41].…”

Section: Discussionmentioning

confidence: 99%

Ropivacaine Inhibits Wound Healing by Suppressing the Proliferation and Migration of Keratinocytes via the PI3K/Akt/mTOR Pathway

Sun

et al. 2021

Preprint

View full text Add to dashboard Cite

Background After surgery, millions of people suffer from delayed healing or wound dehiscence with subsequent severe complications, even death. Previous studies have reported that ropivacaine exhibits anti-proliferative and anti-migratory activities on numerous cells. Whether ropivacaine is able to influence the proliferation and migration of keratinocytes is still unclear. This study aimed to investigate the effect of ropivacaine and migration on keratinocytes and its underlying molecular mechanism. Methods Adult male Sprague-Dawley rats were allocated to establish wound healing models with or without 0.75% ropivacaine treatment and assessed the epidermal thickness by HE staining. HaCaT cells were cultured to evaluate the effect of ropivacaine on wound healing. The cell proliferation, apoptosis status and migration were detected in vitro. Moreover, western blotting was used to examine expression related with PI3K/AKT/mTOR signaling pathways for molecular studies and the changes in inflammatory factors (IL-6, IL-10, TNF-α) were detected by ELISA. Results In the present study, we found that ropivacaine delayed wound closure in vivo. In vitro experiments, it was demonstrated that ropivacaine significantly inhibited the proliferation and migration of HaCaT cells via the suppression of PI3K/Akt/mTOR signaling pathway. Activation of PI3K/Akt/mTOR signaling pathway reversed the effects of ropivacaine on the proliferation and migration of HaCaT cells. Furthermore, ropivacaine contributed to the release of pro-inflammatory cytokines (IL-6 and TNF-α) and inhibited the secretion of anti-inflammatory cytokines of keratinocytes (IL-10). Conclusions Our research demonstrated that ropivacaine treatment showed a more decreased wound closure rate. Mechanistically, we found that ropivacaine suppressed the proliferation and migration of keratinocytes and altered the expression of cytokines by inhibiting PI3K/AKT/mTOR pathway.

show abstract

Plasma endothelial cells-derived extracellular vesicles promote wound healing in diabetes through YAP and the PI3K/Akt/mTOR pathway

Cited by 71 publications

References 39 publications

Yap1-2 Isoform Is the Primary Mediator in TGF-β1 Induced EMT in Pancreatic Cancer

Yap1-2 Isoform Is the Primary Mediator in TGF-β1 Induced EMT in Pancreatic Cancer

Extracellular Vesicles in Skin Wound Healing

Ropivacaine Inhibits Wound Healing by Suppressing the Proliferation and Migration of Keratinocytes via the PI3K/Akt/mTOR Pathway

Contact Info

Product

Resources

About