Endothelial cells induce degradation of ECM through enhanced secretion of MMP14 carried on extracellular vesicles in venous malformation

Chen, Gao-Hong; Yang, Jiegang; Xia, Hou-Fu; Zhang, Lin‐Zhou; Chen, Yin-Hsueh; Wang, Kui-Ming; Xu, Dehong; Wu, Lian-Zhi; Zhao, Yi‐Fang; Chen, Gang

doi:10.1007/s00441-022-03657-2

Cited by 5 publications

(5 citation statements)

References 29 publications

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“…Moreover, the study highlighted an upregulation of genes involved in ECM organization and remodelling, aligning with our identification of the related gene ontology term, "cellsubstrate adhesion." These included ADAMTS18, MMP10, MME and various ECM proteins, which have been observed in patient samples before [58,59]. This consistency underscores the relevance and utility of our model for investigating vascular pathologies linked to TIE2 mutations.…”

Section: Discussionsupporting

confidence: 65%

Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells

Lazovic,

Nguyen,

Ansarizadeh

et al. 2024

Angiogenesis

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Induced pluripotent stem cell (iPSC) derived endothelial cells (iECs) have emerged as a promising tool for studying vascular biology and providing a platform for modelling various vascular diseases, including those with genetic origins. Currently, primary ECs are the main source for disease modelling in this field. However, they are difficult to edit and have a limited lifespan. To study the effects of targeted mutations on an endogenous level, we generated and characterized an iPSC derived model for venous malformations (VMs). CRISPR-Cas9 technology was used to generate a novel human iPSC line with an amino acid substitution L914F in the TIE2 receptor, known to cause VMs. This enabled us to study the differential effects of VM causative mutations in iECs in multiple in vitro models and assess their ability to form vessels in vivo. The analysis of TIE2 expression levels in TIE2L914F iECs showed a significantly lower expression of TIE2 on mRNA and protein level, which has not been observed before due to a lack of models with endogenous edited TIE2L914F and sparse patient data. Interestingly, the TIE2 pathway was still significantly upregulated and TIE2 showed high levels of phosphorylation. TIE2L914F iECs exhibited dysregulated angiogenesis markers and upregulated migration capability, while proliferation was not affected. Under shear stress TIE2L914F iECs showed reduced alignment in the flow direction and a larger cell area than TIE2WT iECs. In summary, we developed a novel TIE2L914F iPSC-derived iEC model and characterized it in multiple in vitro models. The model can be used in future work for drug screening for novel treatments for VMs.

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Section: Discussionsupporting

confidence: 65%

Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells

Lazovic,

Nguyen,

Ansarizadeh

et al. 2024

Angiogenesis

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“…Size change may only be an incidental phenotype of the dramatically different sEVs derived from VMECs, from composition to function. Our previous study not only reported multiple‐dysregulated signaling pathways in VMs, but also demonstrated more enriched MMP14 in sEVs derived from VMECs when compared with that of normal ECs (Chen et al, 2014, 2022; Ren et al, 2014; Zhu et al, 2022). We also reported the changed role of sEVs derived from VPS4B‐deficient ECs in regulating the angiogenesis of HUVECs here.…”

Section: Discussionmentioning

confidence: 92%

“…Current studies summarized that parental cells could modify sEV biogenesis following their physiological state to educate the external environment (Colombo et al, 2014). Our previous works have demonstrated that the production and functions of EC‐derived sEVs in VMs are different from those in healthy subjects (Chen et al, 2022; Zhu et al, 2017). This study further found that the size of EC‐derived sEVs in VMs was larger than that of normal individuals, which was correlated with the abnormal AKT/VPS4B signaling in ECs.…”

Section: Discussionmentioning

confidence: 95%

“…Our results in this study demonstrated that abnormal AKT phosphorylation could downregulate the expression level of VPS4B, leading to the enlarged size of sEVs in VMs. More than that, our previous study has demonstrated that excessively activated AKT signaling promoted the increased secretion of sEV-MMP14 by upregulating the expression level of Rab27A in VMs (Chen et al, 2022). Lots of studies also focused on the role of the AKT signaling in the sEV-mediated intercellular communication.…”

Section: Discussionmentioning

confidence: 99%

“…Many exciting discoveries have greatly expanded our understanding of sEV, including the endosomal sorting complex required for transport (ESCRT)-dependent sEV biogenesis, the GTPase-mediated sEV transportation, the ESCRT-independent sEV production and so on (Baietti et al, 2012;Wei et al, 2021). Our previous works have reported the increased sEV production and the Rab27-regulated sEV MMP14 secretion in VMs (Chen et al, 2022;Zhu et al, 2017). However, our current knowledge is still far away from fully portraying the change of sEV-mediated intercellular communication in VMs.…”

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confidence: 99%

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p‐AKT/VPS4B regulates the small extracellular vesicle size in venous malformation endothelial cells

et al. 2023

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ObjectiveSmall extracellular vesicle (sEV)‐mediated intercellular communication is increasingly the key for the understanding of venous malformations (VMs). This study aims to clarify the detailed changes of sEVs in VMs.Subjects and MethodsFifteen VM patients without treatment history and twelve healthy donors were enrolled in the study. sEVs were isolated from both fresh lesions and cell supernatant, and were examined by western blotting, nanoparticle tracking analysis and transmission electron microscopy. Western blot analysis, immunohistochemistry and immunofluorescence were adopted to screening candidate regulator of sEV size. Specific inhibitors and siRNA were employed to validate the role of dysregulated p‐AKT/vacuolar protein sorting‐associated protein 4B (VPS4B) signaling on the size of sEVs in endothelial cells.ResultsThe size of sEVs derived from both VM lesion tissues and cell model was significantly increased. VPS4B, whose expression level was mostly significantly downregulated in VM endothelial cells, was responsible for the size change of sEVs. Targeting abnormal AKT activation corrected the size change of sEVs by recovering the expression level of VPS4B.ConclusionDownregulated VPS4B in endothelial cells, resulted from abnormally activated AKT signaling, contributed to the increased size of sEVs in VMs.

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Spatiotemporal characteristics of tissue derived small extracellular vesicles is associated with tumor relapse and anti-PD-1 response

Fu,

Xiong,

Xia

et al. 2024

Cancer Letters

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Endothelial cells induce degradation of ECM through enhanced secretion of MMP14 carried on extracellular vesicles in venous malformation

Cited by 5 publications

References 29 publications

Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells

Human iPSC and CRISPR targeted gene knock-in strategy for studying the somatic TIE2L914F mutation in endothelial cells

p‐AKT/VPS4B regulates the small extracellular vesicle size in venous malformation endothelial cells

Spatiotemporal characteristics of tissue derived small extracellular vesicles is associated with tumor relapse and anti-PD-1 response

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