Glioma-derived exosomes drive the differentiation of neural stem cells to astrocytes

Abstract

Exosomes appear to be effective inter-cellular communicators delivering several types of molecules, such as proteins and RNAs, suggesting that they could influence neural stem cell (NSC) differentiation. Our RNA sequencing studies demonstrated that the RNAs related to cell proliferation and astrocyte differentiation were upregulated in human mesenchymal stem cells (hMSC) when co-cultured with exosomes obtained from the culture medium of human glioma cells (U87). Metallothionein 3 and elastin genes, which are related to cell proliferation, increased 10 and 7.2 fold, respectively. Expression of genes for astrocyte differentiation, such as tumor growth factor alpha, induced protein 3 of the NOTCH1 family, colony stimulating factor and interleukin 6 of the STAT3 family and Hes family bHLH transcription factor 1 also increased by 2.3, 10, 4.7 and 2.9 fold, respectively. We further examined the effects of these exosomes on rat fetal neural stem cell (rNSC) differentiation using the secreted exosomes from U87 glioma cells or exosomes from U87 cells that were stimulated with interleukin 1β (IL-1β). The rNSCs, extracted from rat brains at embryonic day 14 (E14), underwent a culture protocol that normally leads to predominant (~90%) differentiation to ODCs. However, in the presence of the exosomes from untreated or IL-1β-treated U87 cells, significantly more cells differentiated into astrocytes, especially in the presence of exosomes obtained from the IL-1β-challenged glioma cells. Moreover, glioma-derived exosomes appeared to inhibit rNSC differentiation into ODCs or astrocytes as indicated by a significantly increased population of unlabeled cells. A portion of the resulting astrocytes coexpressed both CD133 and glial fibrillary acidic protein (GFAP) suggesting that exosomes from U87 cells could promote astrocytic differentiation of NSCs with features expected from a transformed cell. Our data clearly demonstrated that exosomes secreted by human glioma cells provide a strong driving force for rat neural stem cells to differentiate into astrocytes,

Xenogenic Neural Stem Cell‐Derived Extracellular Nanovesicles Modulate Human Mesenchymal Stem Cell Fate and Reconstruct Metabolomic Structure

“…Despite being a diverse source of bioactive proteins (growth factors), lipids, metabolites, and genetic materials (mRNAs, miRNAs, and noncoding RNAs) [25] that can stimulate cell differentiation, the use of exosomes to induce cellular differentiation and modulate fate decision has rarely been explored. [26][27][28] Glioma-derived exosomes, [26] exosomes isolated from neuronal cells, [27] and differentiating neuronal cells [28] have been shown to induce MSCs and NSCs into neuron-like cells. However, these early promising approaches only provided the formation of neuritic extensions with a low yield that is far from a complete induction and differentiation.…”

Gold Nanorod Substrate for Rat Fetal Neural Stem Cell Differentiation into Oligodendrocytes

“…We followed our established protocol to differentiate NPCs into ODCs [ 14 , 15 ]. Passage II NPCs were seeded onto a CELLstart-coated T-25 flask (200,000 cells/flask) that consisted of a complete StemPro serum-free medium supplemented with bFGF (15 ng/mL).…”

Current landscape of tumor-derived exosomal ncRNAs in glioma progression, detection, and drug resistance

“… A putative therapeutic target [ 32 ] lncRNA-ATB Upregulated in A172 and U251 cells Precipitation method Accelerated the migration and invasion of glioma cells by the inhibition of miR-204-3p in an Argonaute 2-dependent manner to activate recipient astrocytes A therapeutic target for the treatment of invasive glioma [ 37 ] miR-199a-3p Upregulated in tissues and C6 cells Ultracentrifugation Upregulated by the HIF-1α activation, and then aggravated oxygen-glucose deprivation and the ischemic injury of HT22 cells via repressing mTOR pathway. A potential therapeutic target [ 38 ] miR-10a Upregulated in U87, P3, GL261, and G422 cells Ultracentrifugation Mediated GDE-induced MDSC expansion and activation via targeting RORA A target for MDSCs-based therapy [ 47 ] miR-21 Upregulated in U87, P3, GL261, and G422 cells Ultracentrifugation Mediated GDE-induced MDSC expansion and activation via targeting PTEN A target for MDSCs-based therapy [ 47 ] miR-29a Upregulated in GL261, G422, U87, and P3 Ultracentrifugation Intensified the differentiation and propagation of functional MDSCs by targeting Hbp1 A target for MDSCs-based immunotherapy [ 48 ] miR-92a Upregulated in GL261, G422, U87, and P3 Ultracentrifugation Intensified the differentiation and propagation of functional MDSCs by targeting Prkar1α A target for MDSCs-based immunotherapy [ 48 ] miR-1246 Upregulated in U87MG and U251 cells Ultracentrifugation Mediated H-GDE-induced M2 macrophage polarization via targeting TERF2IP to activate the STAT3 and inhibit the NF-κB signaling pathway A novel diagnostic biomarker for GBM and a potential therapeutic target for antitumor immunotherapy [ 49 ] miR-21 Upregulated in BMDM Ultracentrifugation Promoted proliferation, migration, and invasion as well as inhibit apoptosis of U87 cells by reducing PEG3 Helpful for the diagnosis and treatment of glioma [ 50 ] GBM glioblastoma multiforme, NcRNA non-coding RNA, LncRNA long non-coding RNA, miRN...…”

“…Exosome-mediated interaction between astrocyte and glioma conferred a chemoresistance property for the relapse of glioma. Sharma et al further investigated that GDEs were the potential driving force in promoting the differentiation of rNSCs to astrocytes [ 38 ]. GDEs induced the astrocytes activation and could shuttle lncRNA-ATB to astrocytes [ 39 ].…”