Exosomes derived from microRNA-512-5p-transfected bone mesenchymal stem cells inhibit glioblastoma progression by targeting JAG1

Abstract

In this study, we demonstrate that bone mesenchymal stem cell (BMSC)-derived exosomes alter tumor phenotypes by delivering miR-512-5p. miR-512-5p was downregulated in glioblastoma tissues and cells, and Jagged 1 (JAG1) was the target gene of miR-512-5p. We clarified the expression patterns of miR-512-5p and JAG1 along with their interactions in glioblastoma. Additionally, we observed that BMSC-derived exosomes could contain and transport miR-512-5p to glioblastoma cells in vitro . BMSC-derived exosomal miR-512-5p inhibited glioblastoma cell proliferation and induced cell cycle arrest by suppressing JAG1 expression. In vivo assays validated the in vitro findings, with BMSC-exosomal miR-512-5p inhibiting glioblastoma growth and prolonging survival in mice. These results suggest that BMSC-derived exosomes transport miR-512-5p into glioblastoma and slow its progression by targeting JAG1. This study reveals a new molecular mechanism for glioblastoma treatment and validates miRNA packaging into exosomes for glioblastoma cell communication.

Application of Mesenchymal Stem Cells in Targeted Delivery to the Brain: Potential and Challenges of the Extracellular Vesicle-Based Approach for Brain Tumor Treatment

“…Mice with orthotopic implantation of GSCs were intraperitoneally administered Exo-miR124 every 2 days, and 50% of animals were still alive at 110 days with complete regression from pathological analysis of surviving mice [ 172 ]. Following this work, many studies on GBM also adopted similar delivery strategies to validate the therapeutic potential of different miRNAs including miR-584 [ 173 ], miR-133b [ 174 ], miR-199a [ 175 ], miR-375 [ 176 ], miR-512-5p [ 177 ], and miR-29a-3p [ 178 ]. All studies chose to genetically engineer the MSCs, either through direct transfection with synthetic miRNAs [ 173 , 174 , 175 ] or using lentiviral transduction to stably and endogenously express the miRNAs [ 176 , 177 , 178 ], and then isolate the secreted EVs.…”

“…Following this work, many studies on GBM also adopted similar delivery strategies to validate the therapeutic potential of different miRNAs including miR-584 [ 173 ], miR-133b [ 174 ], miR-199a [ 175 ], miR-375 [ 176 ], miR-512-5p [ 177 ], and miR-29a-3p [ 178 ]. All studies chose to genetically engineer the MSCs, either through direct transfection with synthetic miRNAs [ 173 , 174 , 175 ] or using lentiviral transduction to stably and endogenously express the miRNAs [ 176 , 177 , 178 ], and then isolate the secreted EVs. Xenograft nude mice were the model of choice, with GBM cells inoculated into the brain via intracranial [ 177 , 178 ] or subcutaneous [ 173 , 174 , 175 , 176 ] injections ( Table 2 ).…”

“…All studies chose to genetically engineer the MSCs, either through direct transfection with synthetic miRNAs [ 173 , 174 , 175 ] or using lentiviral transduction to stably and endogenously express the miRNAs [ 176 , 177 , 178 ], and then isolate the secreted EVs. Xenograft nude mice were the model of choice, with GBM cells inoculated into the brain via intracranial [ 177 , 178 ] or subcutaneous [ 173 , 174 , 175 , 176 ] injections ( Table 2 ).…”

Exosomal transfer of miR-769-5p promotes osteosarcoma proliferation and metastasis by targeting DUSP16

“…However, their effect on tumor growth is controversial [ 17 – 19 ]. BMSCs promote the development of breast cancer and prostate cancer [ 17 ], yet inhibit the progression of glioblastoma and hepatocellular carcinoma [ 18 , 19 ]. Moreover, OS cells may originate from BMSCs, while BMSCs regulate OS metastasis [ 20 ].…”

miR-126 in Extracellular Vesicles Derived from Hepatoblastoma Cells Promotes the Tumorigenesis of Hepatoblastoma through Inducing the Differentiation of BMSCs into Cancer Stem Cells

“…Previous reports have revealed that the association between tumor cells and stem cells in the tumor microenvironment can play a key role in modulating the development of cancer [17,18]. In the tumor environment, BMSCs are often associated with tumor cells to regulate tumorigenesis and metastasis of cancers [19,20].…”