Mechanical loading stimulates bone angiogenesis through enhancing type H vessel formation and downregulating exosomal miR-214-3p from bone marrow-derived mesenchymal stem cells.
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ABSTRACT:
SUBMITTER: Wang X
PROVIDER: S-EPMC7748991 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Emerging evidence indicates that osteoclasts direct osteoblastic bone formation. MicroRNAs (miRNAs) have a crucial role in regulating osteoclast and osteoblast function. However, whether miRNAs mediate osteoclast-directed osteoblastic bone formation is mostly unknown. Here, we show that increased osteoclastic miR-214-3p associates with both elevated serum exosomal miR-214-3p and reduced bone formation in elderly women with fractures and in ovariectomized (OVX) mice. Osteoclast-specific miR-214-3p knock-in mice have elevated serum exosomal miR-214-3p and reduced bone formation that is rescued by osteoclast-targeted antagomir-214-3p treatment. We further demonstrate that osteoclast-derived exosomal miR-214-3p is transferred to osteoblasts to inhibit osteoblast activity in vitro and reduce bone formation in vivo. Moreover, osteoclast-targeted miR-214-3p inhibition promotes bone formation in ageing OVX mice. Collectively, our results suggest that osteoclast-derived exosomal miR-214-3p transfers to osteoblasts to inhibit bone formation. Inhibition of miR-214-3p in osteoclasts may be a strategy for treating skeletal disorders involving a reduction in bone formation.
| S-EPMC4786676 | biostudies-literature
Project description:Mammary cancer incidence varies greatly across species and underlying mechanisms remain elusive. We previously showed that mammosphere-derived epithelial cells from species with low mammary cancer incidence, such as horses, respond to carcinogen 7, 12-Dimethylbenz(a)anthracene-induced DNA damage by undergoing apoptosis, a postulated anti-cancer mechanism. Additionally, we found that miR-214-3p expression in mammosphere-derived epithelial cells is lower in mammary cancer-resistant as compared to mammary cancer-susceptible species. Here we show that increasing miR-214 expression and decreasing expression of its target gene nuclear factor kappa B subunit 1 in mammosphere-derived epithelial cells from horses abolishes 7,12-Dimethylbenz(a)anthracene-induced apoptosis. A direct interaction of miR-214-3p with another target gene, unc-5 netrin receptor A, is also demonstrated. We propose that relatively low levels of miR-214 in mammosphere-derived epithelial cells from mammals with low mammary cancer incidence, allow for constitutive gene nuclear factor kappa B subunit 1 expression and apoptosis in response to 7, 12-Dimethylbenz(a)anthracene. Better understanding of the mechanisms regulating cellular responses to carcinogens improves our overall understanding of mammary cancer resistance mechanisms.
| S-EPMC10547694 | biostudies-literature
Project description:Dendritic cell-derived exosomes have been proven to be efficient adjuvant options for anti-tumor vaccines in cancer immunotherapy. However, their potency in atherosclerosis remains unclear. Here we summarize the association of microRNA-203-3p (miR-203-3p) with dendritic cell-derived exosomes and atherosclerosis. Firstly, dendritic cell-derived exosomes and bone marrow-derived macrophages were isolated, after which expression of miR-203-3p and cathepsin S was determined. After the establishment of atherosclerosis mouse models, gain- and loss-of-function experiments were conducted for the analysis of effects of miR-203-3p and cathepsin S on foam-cell formation, lipid accumulation, collagen deposition and serum total cholesterol. The results found high expression of cathepsin S in atherosclerosis mice and downregulation of miR-203-3p in the serum of atherosclerosis patients and ox-LDL-simulated bone marrow-derived macrophages. Cathepsin S was the target gene of miR-203-3p. miR-203-3p transporting from exosomes to bone marrow-derived macrophages resulted in inhibition of cathepsin S expression and atherosclerosis-related phenotypes in bone marrow-derived macrophages, thus alleviating atherosclerosis in mice, and this process was found to involve the p38/MAPK signaling pathway. These findings provided evidence that the transfer of miR-203-3p by dendritic cell-derived exosomes targeted cathepsin S in bone marrow-derived macrophages to attenuate atherosclerosis progression in mice, serving as a promising clinical target for atherosclerosis.
| S-EPMC8221304 | biostudies-literature
Project description:Infiltration by dendritic cells (DCs) is markedly increased in the infarcted area following myocardial infarction (MI), and DC ablation has been shown to impair angiogenesis in mice post‑MI. Exosomes (EXs) have long been known to act as messengers between cells; however, whether EXs derived from DCs can enhance myocardial angiogenesis post‑MI remains unknown. The aim of the present study was to elucidate whether EXs derived from DCs induce myocardial angiogenesis via paracrine signaling post‑MI. In vitro, suspensions of mouse bone marrow‑derived DCs (BMDCs) were incubated with the supernatant of necrotic or normal cultured HL‑1 myocardial cells (as the MI or control group, respectively) for 24 h. EXs isolated from the supernatant of BMDCs were termed DEXs, which were added to primary cultures of rat cardiac microvascular endothelial cells (CMECs), and angiogenesis was evaluated by measuring tube formation and vascular endothelial growth factor (VEGF) expression. In vivo, different groups of DEXs were injected into the infarcted myocardium of MI model mice. Then, angiogenesis was evaluated by measuring the number of vessels and the expression of VEGF and CD31 in the infarcted myocardium using immunohistochemistry. Moreover, the expression profile of microRNAs (miRNAs or miRs) in splenic DCs of MI model mice was analyzed by Affymetrix miRNA 4.0 chip assays, then certified in DEXs by reverse transcription‑quantitative PCR analysis. Finally, miRNA‑loaded DEXs were used to induce tube formation by CMECs and angiogenesis in MI model mice. It was observed that, compared with the control group, DEXs from the MI group significantly upregulated the expression of VEGF in CMECs, enhanced tube formation by CMECs, and upregulated the expression of VEGF and CD31 in the infarcted myocardium of MI model mice. miR‑494‑3p and miR‑16a‑5p, which are associated with angiogenesis, were significantly upregulated in splenic DCs of MI model mice by Affymetrix miRNA 4.0 chip assays, miR‑494‑3p was significantly upregulated and highly enriched in DEXs from the MI group compared with the control, and DEX‑miR‑494‑3p enhanced tube formation by CMECs and angiogenesis in mice post‑MI. These results suggest that miR‑494‑3p may be secreted from DCs via EXs and promotes angiogenesis post‑MI. These findings indicate a novel DEX‑based approach to the treatment of MI.
| S-EPMC7723512 | biostudies-literature
Project description:The limb-bud and heart (LBH) gene was reported to suppress nasopharyngeal carcinoma (NPC) progression in our previous study. Distant metastasis predominantly accounts for the unsatisfactory prognosis of NPC treatment, in which epithelial-mesenchymal transition (EMT) and tumor angiogenesis are of great significance. The roles of exosomes in mediating NPC progression have been highlighted in recent researches, and attempts have been made to explore the clinical application of NPC exosomes. Here we investigated the function of the LBH gene in NPC exosomes, and its potential mechanism. NPC xenografts were constructed, showing that vascular endothelial growth factor A (VEGFA) expression and neovascularity were attenuated by LBH overexpression, together with diminished EMT progression. NPC-derived exosomes were isolated, identified and applied for in vitro/in vivo experiments, and the exosomal distribution of LBH was elevated in exosomes derived from LBH-upregulated cells. Ectopic LBH, αB-crystallin (CRYAB) and VEGFA expression was induced by lentiviral infection or plasmid transfection to explore their functions in modulating EMT and angiogenesis in NPC. The addition of LBH+ NPC exosomes during a Matrigel plug assay in mice suppressed in vivo angiogenesis, and the treatment of human umbilical vein endothelial cells (HUVECs) with LBH+ NPC exosomes inhibited cellular proliferation, migration and tube formation. The interactions among LBH, CRYAB and VEGFA were confirmed by colocalization and fluorescence resonance energy transfer (FRET) assays, and extracellular VEGFA secretion from both HUVECs and NPC cells under the treatment with LBH+ NPC exosomes was diminished according to ELISA results. We concluded that exosomal LBH inhibits EMT progression and angiogenesis in the NPC microenvironment, and that its effects are partially implemented by modulation of VEGFA expression, secretion and related signaling. Thus, LBH could serve as a promising therapeutic target in VEGFA-focused NPC treatment.
| S-EPMC8692147 | biostudies-literature
Project description:BACKGROUND:Exosomes play crucial roles in regulating the crosstalk between normal and cancer cells in the tumor microenvironment, and in regulating cancer proliferation, migration and invasion through their cargo molecules. METHODS:We analyzed the pro-invasiveness of exosomal circRNA-100,338 in HCC using the transwell invasion assay. The co-culture of human umbilical vein endothelial cells (HUVEC) and exosomes derived from HCC cell lines were used to evaluate the impact of HCC derived exosomes on HUVEC. Nude mice models were used to validate the findings in vitro. Clinically, quantitative RT-PCR was used to quantify the expression of serum exosomal circRNA-100,338 in HCC patients at both pre-surgery within one week and post-surgery within three weeks. RESULTS:We aim to investigate the pro-invasive role of exosomal circRNA-100,338 in HCC metastasis. We for the first time demonstrated that circRNA-100,338 was highly expressed in both highly metastatic HCC cells and their secreted exosomes. The transwell invasion assay showed that the overexpression or knockdown of exosomal circRNA-100,338 significantly enhanced or reduced the invasive abilities of HCC cells. Subsequently, in vitro and in vivo assays showed that exosomal circRNA-100,338 affected the cell proliferation, angiogenesis, permeability, and vasculogenic mimicry (VM) formation ability of human umbilical vein endothelial cells (HUVEC), and tumor metastasis. Furthermore, we also observed that the persistent high expression of exosomal circRNA-100,338 in serum of HCC patients who underwent curative hepatectomy may be a risk indicator of pulmonary metastasis and poor survival. CONCLUSIONS:Our findings indicated that metastatic ability of HCC cells could be enhanced by transferring exosomal circRNA-100,338 to recipient HUVECs, which could affect proangiogenic activity by regulating angiogenesis.
| S-EPMC6979009 | biostudies-literature
Project description:Several growth factors are expressed in distinct temporal and spatial patterns during fracture repair. Of these, vascular endothelial growth factor, VEGF, is of particular interest because of its ability to induce neovascularization (angiogenesis). To determine whether VEGF is required for bone repair, we inhibited VEGF activity during secondary bone healing via a cartilage intermediate (endochondral ossification) and during direct bone repair (intramembranous ossification) in a novel mouse model. Treatment of mice with a soluble, neutralizing VEGF receptor decreased angiogenesis, bone formation, and callus mineralization in femoral fractures. Inhibition of VEGF also dramatically inhibited healing of a tibial cortical bone defect, consistent with our discovery of a direct autocrine role for VEGF in osteoblast differentiation. In separate experiments, exogenous VEGF enhanced blood vessel formation, ossification, and new bone (callus) maturation in mouse femur fractures, and promoted bony bridging of a rabbit radius segmental gap defect. Our results at specific time points during the course of healing underscore the role of VEGF in endochondral vs. intramembranous ossification, as well as skeletal development vs. bone repair. The responses to exogenous VEGF observed in two distinct model systems and species indicate that a slow-release formulation of VEGF, applied locally at the site of bone damage, may prove to be an effective therapy to promote human bone repair.
| S-EPMC124965 | biostudies-literature
Project description:BackgroundNon-small cell lung cancer (NSCLC) is one of the most malignant cancers worldwide and its pathogenesis is not completely clear. In this study, we explored the functions and mechanisms of exosomes transferring miR-3180-3p in NSCLC progression.MethodsThe expression levels of miR-3180-3p in NSCLC tissues and paracarcinoma tissues was obtained from the GEO database (GEO: GSE53882). Exosomes derived from A549 cells were identified. Proliferation, migration and invasion were measured after treatment with exosomal miR-3180-3p or transfection using miR-3180-3p mimics. The relationship between miR-3180-3p and forkhead box P4 (FOXP4) was predicted using a bioinformatic tool and measured using a dual-luciferase reporter gene assay and western blotting. Finally, a mouse xenograft model of NSCLC cells was established to verify the function of exosomal miR-3180-3p in vivo.ResultsWe found that miR-3180-3p decreased in both NSCLC cell lines and patient tissues. Overexpression of miR-3180-3p or treatment with exosomal miR-3180-3p significantly suppressed cell proliferation and metastasis in NSCLC cell lines. Subsequently, we found miR-3180-3p downregulated FOXP4 protein expression levels. Furthermore, the volumes and weights of nude mouse tumors expressing exosomal miR-3180-3p were significantly reduced.ConclusionsExosomal miR-3180-3p suppresses NSCLC progression by downregulating FOXP4 expression.Key pointsSIGNIFICANT FINDINGS OF THE STUDY: We found that exosomal miR-3180-3p suppressed NSCLC progression and also identified a miR-3180-3p target gene. These findings provide a foundation to determine innovative therapeutic strategies.What this study addsThis study contributes to research investigating exosomal containing miRNAs.
| S-EPMC7862798 | biostudies-literature
Project description:AbstractTumor-derived exosomes have been shown to play a key role in organ-specific metastasis, and the androgen receptor regulates prostate cancer (PCa) progression. It is unclear whether the androgen receptor regulates the recruitment of prostate cancer cells to the bone microenvironment, even bone metastases, through exosomes. Here, we found that exosomes isolated from PCa cells after knocking down androgen receptor (AR) or enzalutamide treatment can facilitate the migration of prostate cancer cells to osteoblasts. In addition, AR silencing or treatment with the AR antagonist enzalutamide may increase the expression of circular RNA-deoxyhypusine synthase (circ-DHPS) in PCa cells, which can be transported to osteoblasts by exosomes. Circ-DHPS acts as a competitive endogenous RNA (ceRNA) against endogenous miR-214-3p to promote C-C chemokine ligand 5 (CCL5) levels in osteoblasts. Increasing the level of CCL5 in osteoblasts could recruit more PCa cells into the bone microenvironment. Thus, blocking the circ-DHPS/miR-214-3p/CCL5 signal may decrease exosome-mediated migration of prostate cancer cells to osteoblasts.
| S-EPMC10919426 | biostudies-literature
Project description:BackgroundAngiogenesis is essential for tissue repair in ischemic diseases, relying on glycolysis as its primary energy source. Prolyl 4-hydroxylase subunit alpha 1 (P4HA1), the catalytic subunit of collagen prolyl 4-hydroxylase, is a glycolysis-related gene in cancers. However, its role in glycolysis-induced angiogenesis remains unclear.MethodsP4HA1 expression was modulated using adenoviruses. Endothelial angiogenesis was evaluated through 5-ethynyl-2'-deoxyuridine incorporation, transwell migration, and tube formation assays in vitro. In vivo experiments measured blood flow and capillary density in the hindlimb ischemia (HLI) model. Glycolytic stress assays, glucose uptake, lactate production, and quantitative reverse transcription-polymerase chain reaction (RT-PCR) were employed to assess glycolytic capacity. Transcriptome sequencing, validated by western blotting and RT-PCR, was utilized to determine underlying mechanisms.ResultsP4HA1 was upregulated in endothelial cells under hypoxia and in the HLI model. P4HA1 overexpression promoted angiogenesis in vitro and in vivo, while its knockdown had the opposite effect. P4HA1 overexpression reduced cellular α-ketoglutarate (α-KG) levels by consuming α-KG during collagen hydroxylation. Downregulation of α-KG reduced the protein level of a DNA dioxygenase, ten-eleven translocation 2 (TET2), and its recruitment to the fructose-1,6-biphosphatase (FBP1) promoter, resulting in decreased FBP1 expression. The decrease in FBP1 enhanced glycolytic metabolism, thereby promoting endothelial angiogenesis.ConclusionsHypoxia-induced endothelial P4HA1 overexpression enhanced angiogenesis by promoting glycolytic metabolism reprogramming through the P4HA1/α-KG/TET2/FBP1 pathway. The study's findings underscore the significance of P4HA1 in post-ischemic angiogenesis, suggesting its therapeutic potential for post-ischemic tissue repair.
| S-EPMC10797932 | biostudies-literature