scholarly journals miRNA-1246 in Extracellular Vesicles Secreted from Metastatic Tumor Induces Drug Resistance in Tumor Endothelial Cells

2020 ◽  
Author(s):  
Chisaho Torii ◽  
Nako Maishi ◽  
Taisuke Kawamoto ◽  
Masahiro Morimoto ◽  
Kosuke Akiyama ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Endothelial Cells ◽  
Induced Resistance ◽  
Extracellular Vesicles ◽  
Metastatic Tumor ◽  
Metastatic Tumors ◽  
Glycoprotein P ◽  
Tumor Endothelial Cells

Abstract Background: Tumor endothelial cells (TECs) reportedly exhibit altered phenotypes. We have demonstrated that TECs acquire drug resistance with the upregulation of p-glycoprotein (p-gp, ABCB1), contrary to traditional assumptions. Furthermore, p-gp expression was higher in TECs of highly metastatic tumors than in those of low metastatic tumors. However, the detailed mechanism of differential p-gp expression in TECs remains unclear. Methods: miRNA was identified in highly metastatic tumor extracellular vesicles (EVs) and the roles of miRNA in endothelial cell resistance were analyzed in vitro and in vivo. Results: In the present study, we found that treatment of highly metastatic tumor-conditioned medium induced resistance to 5-fluorouracil (5-FU) with interleukin-6 (IL-6) upregulation in endothelial cells (ECs). Among the soluble factors secreted from highly metastatic tumors, we focused on extracellular vesicles (EVs) and determined that miR-1246 was contained at a higher level in highly metastatic tumor EVs than in low metastatic tumor EVs. Furthermore, miR-1246 was transported via the EVs into ECs and induced IL-6 expression. Upregulated IL-6 induced resistance to 5-FU with STAT3 and Akt activation in ECs in an autocrine manner. Conclusions: These results suggested that highly metastatic tumors induce drug resistance in ECs by transporting miR-1246 through EVs.

scholarly journals miRNA-1246 in extracellular vesicles secreted from metastatic tumor induces drug resistance in tumor endothelial cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chisaho Torii ◽  
Nako Maishi ◽  
Taisuke Kawamoto ◽  
Masahiro Morimoto ◽  
Kosuke Akiyama ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Endothelial Cells ◽  
Induced Resistance ◽  
Extracellular Vesicles ◽  
Metastatic Tumor ◽  
Metastatic Tumors ◽  
Glycoprotein P ◽  
Tumor Endothelial Cells

AbstractTumor endothelial cells (TECs) reportedly exhibit altered phenotypes. We have demonstrated that TECs acquire drug resistance with the upregulation of P-glycoprotein (P-gp, ABCB1), contrary to traditional assumptions. Furthermore, P-gp expression was higher in TECs of highly metastatic tumors than in those of low metastatic tumors. However, the detailed mechanism of differential P-gp expression in TECs remains unclear. miRNA was identified in highly metastatic tumor extracellular vesicles (EVs) and the roles of miRNA in endothelial cell resistance were analyzed in vitro and in vivo. In the present study, we found that treatment of highly metastatic tumor-conditioned medium induced resistance to 5-fluorouracil (5-FU) with interleukin-6 (IL-6) upregulation in endothelial cells (ECs). Among the soluble factors secreted from highly metastatic tumors, we focused on EVs and determined that miR-1246 was contained at a higher level in highly metastatic tumor EVs than in low metastatic tumor EVs. Furthermore, miR-1246 was transported via the EVs into ECs and induced IL-6 expression. Upregulated IL-6 induced resistance to 5-FU with STAT3 and Akt activation in ECs in an autocrine manner. These results suggested that highly metastatic tumors induce drug resistance in ECs by transporting miR-1246 through EVs.

scholarly journals miRNA-1246 in Extracellular Vesicles Secreted from Metastatic Tumor Induces Drug Resistance in Tumor Endothelial Cells

2020 ◽  
Author(s):  
Chisaho Torii ◽  
Nako Maishi ◽  
Taisuke Kawamoto ◽  
Masahiro Morimoto ◽  
Kosuke Akiyama ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Endothelial Cells ◽  
Extracellular Vesicles ◽  
Metastatic Tumor ◽  
Tumor Endothelial Cells

Abstract The authors have withdrawn this preprint due to author disagreement.

Factor VIIa induces extracellular vesicles from the endothelium: A potential mechanism for its hemostatic effect

Blood ◽  
2021 ◽  
Author(s):  
Kaushik Das ◽  
Shiva Keshava ◽  
Shabbir A Ansari ◽  
Vijay Kumar Reddy Kondreddy ◽  
Charles Esmon ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Extracellular Vesicles ◽  
Factor Viia ◽  
Mutant Mice ◽  
In Vivo Studies ◽  
Cell Protein ◽  
Wild Type ◽  
Hemostatic Effect

Recombinant FVIIa (rFVIIa) is used as a hemostatic agent to treat bleeding disorders in hemophilia patients with inhibitors and other groups of patients. Our recent studies showed that FVIIa binds endothelial cell protein C receptor (EPCR) and induces protease-activated receptor 1 (PAR1)-mediated biased signaling. The importance of FVIIa-EPCR-PAR1-mediated signaling in hemostasis is unknown. In the present study, we show that FVIIa induces the release of extracellular vesicles (EVs) from endothelial cells both in vitro and in vivo. Silencing of EPCR or PAR1 in endothelial cells blocked the FVIIa-induced generation of EVs. Consistent with these data, FVIIa treatment enhanced the release of EVs from murine brain endothelial cells isolated from wild-type, EPCR overexpressors, and PAR1-R46Q mutant mice, but not EPCR-deficient or PAR1-R41Q mutant mice. In vivo studies revealed that administration of FVIIa to wild-type, EPCR overexpressors, and PAR1-R46Q mutant mice, but not EPCR-deficient or PAR1-R41Q mutant mice, increase the number of circulating EVs. EVs released in response to FVIIa treatment exhibit enhanced procoagulant activity. Infusion of FVIIa-generated EVs and not control EVs to platelet-depleted mice increased thrombin generation at the site of injury and reduced blood loss. Administration of FVIIa-generated EVs or generation of EVs endogenously by administering FVIIa augmented the hemostatic effect of FVIIa. Overall, our data reveal that FVIIa treatment, through FVIIa-EPCR-PAR1 signaling, releases EVs from the endothelium into the circulation, and these EVs contribute to the hemostatic effect of FVIIa.

scholarly journals Hypoxia Inducible Factor-1α Overexpression Enhances the Efficacy of Mesenchymal Stem Cells Derived Extracellular Vesicles for Cardiac Repair After Myocardial Infarction

2021 ◽  
Author(s):  
Qingjie Wang ◽  
Le Zhang ◽  
Zhiqin Sun ◽  
Boyu Chi ◽  
Ailin Zou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Mesenchymal Stem Cells ◽  
Cardiac Function ◽  
Extracellular Vesicles ◽  
Biological Effects ◽  
Hypoxia Inducible Factor ◽  
Sprague Dawley

Abstract Aims Naturally secreted extracellular vesicles (EVs) play important roles in stem-mediated cardioprotection. This study aimed to investigate the cardioprotective function and underlying mechanisms of EVs derived from HIF-1a engineered mesenchymal stem cells (MSCs) in a rat model of AMI.Methods and Results EVs isolated from HIF-1a engineered MSCs (HIF-1a-EVs) and control MSCs (MSCs-EVs) were prepared. In in vitro experiments, the EVs were incubated with cardiomyocytes and endothelial cells exposed to hypoxia and serum deprivation (H/SD); in in vivo experiments, the EVs were injected in the acutely infarcted hearts of Sprague-Dawley rats. Compared with MSCs-EVs, HIF-1a-EVs significantly inhibited the apoptosis of cardiomyocytes and enhanced angiogenesis of endothelial cells; meanwhile, HIF-1a-EVs also significantly shrunk fibrotic area and strengthened cardiac function in infarcted rats. After treatment with EVs/RGD-biotin hydrogels, we observed longer retention, higher stability in HIF-1a-EVs, and stronger cardiac function in the rats. Quantitative real-time PCR (qRT-PCR) displayed that miRNA-221-3p was highly expressed in HIF-1a-EVs. After miR-221-3p was inhibited in HIF-1a-EVs, the biological effects of HIF-1a EVs on apoptosis and angiogenesis were attenuated.Conclusion EVs released by MSCs with HIF-1a overexpression can promote the angiogenesis of endothelial cells and the apoptosis of cardiomyocytes via upregulating the expression of miR-221-3p. RGD hydrogels can enhance the therapeutic efficacy of HIF-1a engineered MSC-derived EVs.

scholarly journals Extracellular Vesicles Derived From Human Corneal Endothelial Cells Inhibit Proliferation of Human Corneal Endothelial Cells

2021 ◽  
Author(s):  
Mohit Parekh ◽  
Hefin Rhys ◽  
Tiago Ramos ◽  
Stefano Ferrari ◽  
Sajjad Ahmad
Keyword(s):  
Endothelial Cells ◽  
Extracellular Vesicles ◽  
Ex Vivo ◽  
Treatment Options ◽  
Proliferative Capacity ◽  
Corneal Endothelial Cells ◽  
Human Corneal Endothelial Cells ◽  
The Media

Abstract Corneal endothelial cells (CEnCs) are a monolayer of hexagonal cells that are responsible for maintaining the function and transparency of the cornea. Damage or dysfunction of CEnCs could lead to blindness. Human CEnCs (HCEnCs) have shown limited proliferative capacity in vivo hence, their maintenance is crucial. Extracellular vesicles (EVs), are responsible for inter- and intra-cellular communication, proliferation, cell-differentiation, migration, and many other complex biological processes. Therefore, we investigated the effect of EVs (derived from human corneal endothelial cell line – HCEC-12) on corneal endothelial cells. HCEC-12 cells were starved with serum-depleted media for 72 hours. The media was ultracentrifuged at 100,000xg to isolate the EVs. EV counting, characterization, internalization and localization were performed using NanoSight, flow cytometry, Dil labelling and confocal microscopy respectively. HCEC-12 and HCEnCs were cultured with media supplemented with EVs. Extracted EVs showed a homogeneous mixture of exosomes and microvesicles. Cells with EVs decreased the proliferation rate; increased apoptosis and cell size; showed poor wound healing response in vitro and on ex vivo human, porcine, and rabbit CECs. Thirteen miRNAs were found in the EV sample using next generation sequencing. We observed that increased cellular uptake of EVs by CECs limit the proliferative capacity of HCEnCs. These preliminary data may help in understanding the pathology of corneal endothelial dysfunction and provide further insights in the development of future therapeutic treatment options.

PAHs increase the production of extracellular vesicles both in vitro in endothelial cells and in vivo in urines from rats

2019 ◽  
Vol 255 ◽  
pp. 113171 ◽  
Author(s):  
Manon Le Goff ◽  
Dominique Lagadic-Gossmann ◽  
Remi Latour ◽  
Normand Podechard ◽  
Nathalie Grova ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Extracellular Vesicles

scholarly journals Circulating extracellular vesicles from individuals at high-risk of lung cancer induce pro-tumorigenic conversion of stromal cells through transfer of miR-126 and miR-320

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Francesca Pontis ◽  
Luca Roz ◽  
Mavis Mensah ◽  
Miriam Segale ◽  
Massimo Moro ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Endothelial Cells ◽  
High Risk ◽  
Cancer Patients ◽  
Extracellular Vesicles ◽  
In Vivo Models ◽  
Lung Cancer Patients

Abstract Background Extracellular vesicles (EVs) containing specific subsets of functional biomolecules are released by all cell types and analysis of circulating EVs can provide diagnostic and prognostic information. To date, little is known regarding the role of EVs both as biomarkers and potential key players in human lung cancer. Methods Plasma EVs were isolated from 40 cancer-free heavy-smokers classified according to a validated 24-microRNA signature classifier (MSC) at high (MSCpos-EVs) or low (MSCneg-EVs) risk to develop lung cancer. EVs origin and functional properties were investigated using in vitro 3D cultures and in vivo models. The prognostic value of miRNAs inside EVs was assessed in training and in validation cohorts of 54 and 48 lung cancer patients, respectively. Results Different membrane composition, biological cargo and pro-tumorigenic activity were observed in MSCpos vs MSCneg-EVs. Mechanistically, in vitro and in vivo results showed that miR-126 and miR-320 from MSCpos-EVs increased pro-angiogenic phenotype of endothelial cells and M2 polarization of macrophage, respectively. MSCpos-EVs prompted 3D proliferation of non-tumorigenic epithelial cells through c-Myc transfer. Moreover, hypoxia was shown to stimulate the secretion of EVs containing c-Myc from fibroblasts, miR-126-EVs from endothelial cells and miR-320-EVs from granulocytes. Lung cancer patients with higher levels of mir-320 into EVs displayed a significantly shorter overall survival in training [HR2.96] and validation sets [HR2.68]. Conclusion Overall our data provide a new perspective on the pro-tumorigenic role of circulating EVs in high risk smokers and highlight the significance of miR-320-EVs as a new prognostic biomarker in lung cancer patients.

scholarly journals Identification of Angiogenic Cargo in Extracellular Vesicles Secreted from Human Adipose Tissue-Derived Stem Cells and Induction of Angiogenesis In Vitro and In Vivo

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 495
Author(s):  
Prakash Gangadaran ◽  
Ramya Lakshmi Rajendran ◽  
Ji Min Oh ◽  
Eun Jung Oh ◽  
Chae Moon Hong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Endothelial Cells ◽  
Adipose Tissue ◽  
Blood Vessels ◽  
Extracellular Vesicles ◽  
Human Adipose Tissue ◽  
Antibody Array ◽  
Angiogenic Proteins

Angiogenesis is defined as the generation of new blood vessels or the sprouting of endothelial cells from a pre-existing vascular network. Angiogenesis occurs during the growth and development of an organism, the response of organs or tissues to injury, and during cancer development and progression. The majority of studies on stem-cell-derived extracellular vesicles (EVs) have used cell lines, and have primarily focused on well-known solitary proteins. Here, we isolated stem cells from human adipose tissue (ADSCs), and we isolated EVs from them (ADSC-EVs). The ADSC-EVs were characterised and 20 angiogenic proteins were analysed using an angiogenic antibody array. Furthermore, we analysed the ability of ADSC-EVs to induce angiogenesis in vitro and in vivo. ADSC-EVs were positive for CD81 and negative for GM130, calnexin, and cytochrome-C. ADSC-EVs showed typical EV spherical morphology and were ~200 nm in size. ADSC-EVs were found to contain angiogenic proteins as cargo, among which interleukin 8 (IL-8) was the most abundant, followed by chemokine (C-C motif) ligand 2 (CCL2), a tissue inhibitor of metalloproteinases 1 (TIMP-1), TIMP-2, and vascular endothelial growth factor-D (VEGF-D). ADSC-EVs treatment increased the proliferation, migration, total vessel length, total number of junctions, and junction density of endothelial cells in vitro. The results of an in vivo Matrigel plug assay revealed that ADSC-EVs induced more blood vessels in the Matrigel compared with the control. These results demonstrate that ADSC-EVs contain angiogenic proteins as cargo and promote angiogenesis in vitro and in vivo. Therefore, ADSC-EVs have potential for therapeutic use in ischaemia.

scholarly journals Neurons can upregulate Cav-1 to increase intake of endothelial cells-derived extracellular vesicles that attenuate apoptosis via miR-1290

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Kang-Yi Yue ◽  
Pei-Ran Zhang ◽  
Min-Hua Zheng ◽  
Xiu-Li Cao ◽  
Yuan Cao ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Extracellular Vesicles ◽  
Neuronal Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cell Communication ◽  
Glucose Deprivation ◽  
Neuronal Protection

AbstractExtracellular vesicles (EVs) including exosomes can serve as mediators of cell–cell communication under physiological and pathological conditions. However, cargo molecules carried by EVs to exert their functions, as well as mechanisms for their regulated release and intake, have been poorly understood. In this study, we examined the effects of endothelial cells-derived EVs on neurons suffering from oxygen-glucose deprivation (OGD), which mimics neuronal ischemia-reperfusion injury in human diseases. In a human umbilical endothelial cell (HUVEC)–neuron coculture assay, we found that HUVECs reduced apoptosis of neurons under OGD, and this effect was compromised by GW4869, a blocker of exosome release. Purified EVs could be internalized by neurons and alleviate neuronal apoptosis under OGD. A miRNA, miR-1290, was highly enriched in HUVECs-derived EVs and was responsible for EV-mediated neuronal protection under OGD. Interestingly, we found that OGD enhanced intake of EVs by neurons cultured in vitro. We examined the expression of several potential receptors for EV intake and found that caveolin-1 (Cav-1) was upregulated in OGD-treated neurons and mice suffering from middle cerebral artery occlusion (MCAO). Knock-down of Cav-1 in neurons reduced EV intake, and canceled EV-mediated neuronal protection under OGD. HUVEC-derived EVs alleviated MCAO-induced neuronal apoptosis in vivo. These findings suggested that ischemia likely upregulates Cav-1 expression in neurons to increase EV intake, which protects neurons by attenuating apoptosis via miR-1290.

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