Circulating exosomal miR-21 mediates HUVEC proliferation and migration through PTEN/PI3K/AKT in Crohn’s disease

Abstract

Background: Angiogenesis and vascular dysfunction play important roles in the occurrence and development of Crohn's disease (CD), but relevant mechanistic research is lacking. This paper aimed to use exosomal technology to elucidate the mechanism of vascular abnormalities in CD.Methods: Ultra-high-speed centrifugation was used to extract circulating exosomes. Electron microscopy, particle size, and biomarker detection were used for exome quality control. MicroRNA 21 (miR-21) levels were determined by quantitative polymerase chain reaction (qPCR). Migration abilities and tubule-forming capacity were assessed by wound healing assay, transwell invasion test, and tube formation assay. Exosome biomarkers and pathway protein levels were determined by western blotting.Results: Our data revealed that the circulating exosomes of patients with CD have a remarkable effect on the proliferation and migration of human umbilical vein endothelial cells (HUVECs), and that exosomal miR-21 levels were highly elevated in exosomes derived from the plasma of CD patients. Exosomes derived from CD patients and miR-21 mimic had more powerful migration abilities and tubule-forming capacity than control groups. miR-21 inhibitors significantly blocked the quick migration and tubule formation of HUVECs induced by CD-exosomes. Western blot analysis revealed that circulating exosome miR-21 in HUVECs might weaken negative regulation of phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) by target-inhibiting phosphatase and tensin homolog (PTEN) and inducing the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF).Conclusions: Circulating exosomal miR-21 mediates HUVEC proliferation and migration through PTEN/PI3K/AKT in CD. Exosomal miR-21 may be a new biomarker or therapeutic target for the treatment of vascular abnormalities in CD.

miR-21 antagonist alleviates colitis and angiogenesis via the PTEN/PI3K/AKT pathway in colitis mice induced by TNBS

“…Blood vessels are one of the largest and most important organs in the human body. We have found that exosomal miR-21 targeting Pten induced activation of the PI3K/AKT pathway and promoted migration and tube formation of human umbilical vein endothelial cells (HUVECs) in our previous study, which may be an important mechanism of abnormal angiogenesis in patients with CD (34). Therefore, we injected agomir-21, an exosomal miRNA analogue, into the tail vein of mice induced by TNBS and found that the miR-21 analogue could aggravate the manifestation of colitis in the model mice, while antagomir-21, an in vivo antagonist of miR-21, could alleviate these manifestations and effectively inhibit mesenteric angiogenesis.…”

“…Therefore, miR-21 may play a positive regulatory role in angiogenesis. Our previous study found that the level of miR-21 in plasma exosomes of patients with active CD was elevated and the miR-21 can activate the PI3K/AKT pathway and promote the migration and tube formation of vascular endothelial cells by targeting inhibition of PTEN (34). We therefore hypothesized that the promoting effect of exosomal miR-21 on abnormal colonic vascular regeneration in CD model mice could be verified at the overall level so as to reveal a new vascular proliferation mechanism in the pathogenesis of CD, and that the therapeutic effect of antagomir-21, a specific miR-21 antagonist in vivo, on CD model mice could be preliminarily verified through the functional loss of miRNA in vivo, which could provide a further theoretical basis for the application of miRNA or miRNA antagonists in clinical practice.…”

The combination of a 3D-Printed porous Ti–6Al–4V alloy scaffold and stem cell sheet technology for the construction of biomimetic engineered bone at an ectopic site

“…Human umbilical vein endothelial cells (HUVECs) of passages 3–5 used in this experiment were obtained from ScienCell (USA). After 24 ​h of coculture of PT scaffolds and BMSC/BMSC sheets, the supernatant was collected, named conditioned medium derived from BMSCs (BMSC-CM), and used to culture HUVECs to perform angiogenesis assays, such as wound healing and tube formation assays [ 36 ]. First, a wound healing assay was utilized to assess the migration capacity of HUVECs cultured in BMSC-CM.…”

Potential Pathogenic Impact of Cow’s Milk Consumption and Bovine Milk-Derived Exosomal MicroRNAs in Diffuse Large B-Cell Lymphoma

“…In addition to miR-125b-5p, miR-21-5p targets and inhibits TNFAIP3 [ 449 , 450 ]. Furthermore, miR-21 plays an oncogenic role by targeting FOXO1 [ 451 , 452 , 453 ] and PTEN [ 454 , 455 , 456 ], thereby activating the PI3K/AKT/mTORC1 pathway in DLBCL [ 350 ]. B-cell lymphoma/leukemia 11B ( BCL11B ) is another direct target of miR-21 [ 457 ].…”