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Exosomes Derived From MicroRNA-148b-3p-Overexpressing Human Umbilical Cord Mesenchymal Stem Cells Restrain Breast Cancer Progression.

ABSTRACT: Exosomes derived from human umbilical cord mesenchymal stem cells (HUCMSCs) expressing microRNAs (miRs) have been highlighted as important carriers for gene or drug therapy. Hence, this study aimed to explore the role of exosomal miR-148b-3p from HUCMSCs in breast cancer. Clinical samples subjected to RT-qPCR detection revealed that miR-148b-3p was poorly expressed, while tripartite motif 59 (TRIM59) was highly expressed in breast cancer tissues. Online analyses available at miRanda, TargetScan, and miRbase databases revealed that miR-148b-3p could bind to TRIM59, while dual-luciferase reporter gene assay further verified that TRIM59 was a target gene of miR-148b-3p. Next, miR-148b-3p mimic or inhibitor and siRNA against TRIM59 were delivered into the breast cancer cells (MDA-MB-231) to alter the expression of miR-148b-3p and TRIM59 so as to evaluate their respective effects on breast cancer cellular processes. Evidence was obtained demonstrating that miR-148b-3p inhibited cell proliferation, invasion, and migration, but promoted cell apoptosis in breast cancer by down-regulating TRIM59. Next, MDA-MB-231 cells were co-cultured with the exosomes derived from HUCMSCs expressing miR-148b-3p. The results of co-culture experiments demonstrated that HUCMSCs-derived exosomes carrying miR-148b-3p exerted inhibitory effects on MDA-MB-231 progression in vitro. In vivo experimentation further confirmed the anti-tumor effects of HUCMSCs-derived exosomes carrying miR-148b-3p. Taken together, HUCMSC-derived exosomes carrying miR-148b-3p might suppress breast cancer progression, which highlights the potential of exosomes containing miR-148b-3p as a promising therapeutic approach for breast cancer treatment.

SUBMITTER: Yuan L

PROVIDER: S-EPMC6817568 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Exosomes Derived From MicroRNA-148b-3p-Overexpressing Human Umbilical Cord Mesenchymal Stem Cells Restrain Breast Cancer Progression.

Yuan Lei L Liu Yuqiong Y Qu Yunhui Y Liu Lan L Li Huixiang H

Frontiers in oncology 20191022

Exosomes derived from human umbilical cord mesenchymal stem cells (HUCMSCs) expressing microRNAs (miRs) have been highlighted as important carriers for gene or drug therapy. Hence, this study aimed to explore the role of exosomal miR-148b-3p from HUCMSCs in breast cancer. Clinical samples subjected to RT-qPCR detection revealed that miR-148b-3p was poorly expressed, while tripartite motif 59 (TRIM59) was highly expressed in breast cancer tissues. Online analyses available at miRanda, TargetScan, ...[more]

PMID: 31696054

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Project description:Mesenchymal stem cell (MSC) therapy is an innovative approach in diabetes due to its capacity to modulate tissue microenvironment and regeneration of glucose-responsive insulin-producing cells. In this study, we investigated the role of MSC-derived exosomes in pancreatic regeneration and insulin secretion in mice with streptozotocin-induced diabetes. Mesenchymal stem cells (MSCs) were isolated and characterized from umbilical cord blood (UCB). Exosomes were isolated and characterized from these MSCs. Diabetes was induced in male C57Bl/6 mice by streptozotocin (STZ; 40 mg/kg body weight, i.p.) for five consecutive days. The diabetic mice were administered (i.v.) with MSC (1 × 105 umbilical cord blood MSC cells/mice/day), their derived exosomes (the MSC-Exo group that received exosomes derived from 1 × 105 MSC cells/mice/day), or the same volume of PBS. Before administration, the potency of MSCs and their exosomes was evaluated in vitro by T cell activation experiments. After day 7 of the treatments, blood samples and pancreatic tissues were collected. Histochemistry was performed to check cellular architecture and β cell regeneration. In body weight, blood glucose level, and insulin level, cell proliferation assay was done to confirm regeneration of cells after MSC and MSC-Exo treatments. Hyperglycemia was also attenuated in these mice with a concomitant increase in insulin production and an improved histological structure compared to mice in the PBS-treated group. We found increased expression of genes associated with tissue regeneration pathways, including Reg2, Reg3, and Amy2b in the pancreatic tissue of mice treated with MSC or MSC-Exo relative to PBS-treated mice. MicroRNA profiling of MSC-derived exosomes showed the presence of miRs that may facilitate pancreatic regeneration by regulating the Extl3-Reg-cyclinD1 pathway. These results demonstrate a potential therapeutic role of umbilical cord blood MSC-derived exosomes in attenuating insulin deficiency by activating pancreatic islets' regenerative abilities.

Project description:OBJECTIVE:To study the anti- fibrotic effect of human umbilical cord mesenchymal stem cell-derived exosomes (hUCMSC-EXOs) and explore the mechanism. METHODS:Twenty-four C57 BL/6 mice were divided into 4 groups (n=6), including the control group treated with intratracheal injection of saline (3 mg/kg); lung fibrosis model group with intratracheal injection of 1.5 mg/mL bleomycin solution (prepared with saline, 3 mg/kg); EXOs1 group with intratracheal injection of 1.5 mg/mL bleomycin solution (3 mg/kg) and hUCMSC-EXOs (100 ?g/250 ?L, given by tail vein injection on the next day after modeling); and EXOs2 group with intratracheal injection of 1.5 mg/mL bleomycin solution (3 mg/kg) and hUCMSC-EXOs (100 ?g/250 ?L, given by tail vein injection on the 10th day after modeling). At 21 days after modeling, pulmonary index, lung tissue pathology and collagen deposition in the mice were assessed using HE staining and Masson staining. The expression level of TGF-?1 was detected using ELISA, and vimentin, E-cadherin and phosphorylated Smad2/3 (p-Smad2/3) were detected using immunohistochemical staining. CCK8 assay was used to evaluate the effect of hUCMSCEXOs on the viability of A549 cells, and Western blotting was used to detect the expression levels of p-Smad2/3, vimentin, and E-cadherin in the cells. RESULTS:Compared with those in the model group, the mice treated with hUCMSC-EXOs showed significantly reduced the pulmonary index (P < 0.05), collagen deposition, lung tissue pathologies, lowered expressions of TGF-?1 (P < 0.05), vimentin, and p-Smad2/3 and increased expression of E-cadherin. hUCMSC-EXOs given on the second day produced more pronounced effect than that given on the 11th day (P < 0.05). CCK8 assay results showed that hUCMSC-EXOs had no toxic effects on A549 cells (P > 0.05). Western blotting results showed that hUCMSC-EXOs treatment significantly increased the expression of E-cadherin and decreased the expressions of p-Smad2/3 and vimentin in the cells. CONCLUSIONS:hUCMSC-EXOs can alleviate pulmonary fibrosis in mice by inhibiting epithelialmesenchymal transition activated by the TGF-?1/Smad2/3 signaling pathway, and the inhibitory effect is more obvious when it is administered on the second day after modeling.

Dataset Information

Exosomes Derived From MicroRNA-148b-3p-Overexpressing Human Umbilical Cord Mesenchymal Stem Cells Restrain Breast Cancer Progression.

Publications

Exosomes Derived From MicroRNA-148b-3p-Overexpressing Human Umbilical Cord Mesenchymal Stem Cells Restrain Breast Cancer Progression.

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