Glioma-derived exosomes drive the differentiation of neural stem cells to astrocytes
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 astrocyt...
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| creator | Sharma, Krishna D Schaal, Danielle Kore, Rajshekhar A Hamzah, Rabab N Pandanaboina, Sahitya Chetan Hayar, Abdallah Griffin, Robert J Srivatsan, Malathi Reyna, Nathan S Xie, Jennifer Yanhua |
| description | 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 co-expressed 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, uncovering potential pathways and therapeutic targets that might control this aggressive tumor type. |
| doi_str_mv | 10.1371/journal.pone.0234614 |
| format | Article |
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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 co-expressed 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, uncovering potential pathways and therapeutic targets that might control this aggressive tumor type.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0234614</identifier><identifier>PMID: 32649728</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Astrocytes ; Astrocytes - metabolism ; Astrocytes - physiology ; Biology and Life Sciences ; Brain cancer ; Cell culture ; Cell differentiation ; Cell Differentiation - physiology ; Cell growth ; Cell Proliferation ; Cells, Cultured ; Coculture Techniques ; Colony-stimulating factor ; Culture ; Differentiation ; Elastin ; Elastin - metabolism ; Embryos ; Exosomes ; Exosomes - metabolism ; Exosomes - physiology ; Fetuses ; Gene expression ; Gene Expression Regulation - genetics ; Gene sequencing ; Genes ; Glial fibrillary acidic protein ; Glioma ; Glioma - metabolism ; Glioma cells ; Growth factors ; Helix-loop-helix proteins (basic) ; Humans ; IL-1β ; Interleukin 6 ; Interleukin-6 - metabolism ; Medicine and Health Sciences ; Mesenchyme ; Metallothionein ; Metallothionein 3 ; Metastasis ; Morphology ; Nerve Tissue Proteins - metabolism ; Neural stem cells ; Neural Stem Cells - metabolism ; Neural Stem Cells - physiology ; Neurons - metabolism ; Neurosciences ; Notch1 protein ; Oncology ; Primary Cell Culture ; Proteins ; Rats ; Research and Analysis Methods ; Ribonucleic acid ; RNA ; Stat3 protein ; STAT3 Transcription Factor - metabolism ; Stem cell transplantation ; Stem cells ; Therapeutic applications ; Tumors</subject><ispartof>PloS one, 2020-07, Vol.15 (7), p.e0234614-e0234614</ispartof><rights>2020 Sharma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Sharma et al 2020 Sharma et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-88d026143dc84b32d82c78464052fcf03fe7d3b4d9c9515779aacf84e833c7b23</citedby><cites>FETCH-LOGICAL-c526t-88d026143dc84b32d82c78464052fcf03fe7d3b4d9c9515779aacf84e833c7b23</cites><orcidid>0000-0003-3430-0282 ; 0000-0002-3940-2766</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351166/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351166/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32649728$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ulasov, Ilya</contributor><creatorcontrib>Sharma, Krishna D</creatorcontrib><creatorcontrib>Schaal, Danielle</creatorcontrib><creatorcontrib>Kore, Rajshekhar A</creatorcontrib><creatorcontrib>Hamzah, Rabab N</creatorcontrib><creatorcontrib>Pandanaboina, Sahitya Chetan</creatorcontrib><creatorcontrib>Hayar, Abdallah</creatorcontrib><creatorcontrib>Griffin, Robert J</creatorcontrib><creatorcontrib>Srivatsan, Malathi</creatorcontrib><creatorcontrib>Reyna, Nathan S</creatorcontrib><creatorcontrib>Xie, Jennifer Yanhua</creatorcontrib><title>Glioma-derived exosomes drive the differentiation of neural stem cells to astrocytes</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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 co-expressed 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, uncovering potential pathways and therapeutic targets that might control this aggressive tumor type.</description><subject>Animals</subject><subject>Astrocytes</subject><subject>Astrocytes - metabolism</subject><subject>Astrocytes - physiology</subject><subject>Biology and Life Sciences</subject><subject>Brain cancer</subject><subject>Cell culture</subject><subject>Cell differentiation</subject><subject>Cell Differentiation - physiology</subject><subject>Cell growth</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Coculture Techniques</subject><subject>Colony-stimulating factor</subject><subject>Culture</subject><subject>Differentiation</subject><subject>Elastin</subject><subject>Elastin - metabolism</subject><subject>Embryos</subject><subject>Exosomes</subject><subject>Exosomes - metabolism</subject><subject>Exosomes - physiology</subject><subject>Fetuses</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - genetics</subject><subject>Gene sequencing</subject><subject>Genes</subject><subject>Glial fibrillary acidic protein</subject><subject>Glioma</subject><subject>Glioma - metabolism</subject><subject>Glioma cells</subject><subject>Growth factors</subject><subject>Helix-loop-helix proteins (basic)</subject><subject>Humans</subject><subject>IL-1β</subject><subject>Interleukin 6</subject><subject>Interleukin-6 - metabolism</subject><subject>Medicine and Health Sciences</subject><subject>Mesenchyme</subject><subject>Metallothionein</subject><subject>Metallothionein 3</subject><subject>Metastasis</subject><subject>Morphology</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Neural stem cells</subject><subject>Neural Stem Cells - metabolism</subject><subject>Neural Stem Cells - physiology</subject><subject>Neurons - metabolism</subject><subject>Neurosciences</subject><subject>Notch1 protein</subject><subject>Oncology</subject><subject>Primary Cell Culture</subject><subject>Proteins</subject><subject>Rats</subject><subject>Research and Analysis Methods</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sharma, Krishna D</au><au>Schaal, Danielle</au><au>Kore, Rajshekhar A</au><au>Hamzah, Rabab N</au><au>Pandanaboina, Sahitya Chetan</au><au>Hayar, Abdallah</au><au>Griffin, Robert J</au><au>Srivatsan, Malathi</au><au>Reyna, Nathan S</au><au>Xie, Jennifer Yanhua</au><au>Ulasov, Ilya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glioma-derived exosomes drive the differentiation of neural stem cells to astrocytes</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2020-07-10</date><risdate>2020</risdate><volume>15</volume><issue>7</issue><spage>e0234614</spage><epage>e0234614</epage><pages>e0234614-e0234614</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><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 co-expressed 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, uncovering potential pathways and therapeutic targets that might control this aggressive tumor type.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>32649728</pmid><doi>10.1371/journal.pone.0234614</doi><orcidid>https://orcid.org/0000-0003-3430-0282</orcidid><orcidid>https://orcid.org/0000-0002-3940-2766</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2020-07, Vol.15 (7), p.e0234614-e0234614 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2422400258 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Astrocytes Astrocytes - metabolism Astrocytes - physiology Biology and Life Sciences Brain cancer Cell culture Cell differentiation Cell Differentiation - physiology Cell growth Cell Proliferation Cells, Cultured Coculture Techniques Colony-stimulating factor Culture Differentiation Elastin Elastin - metabolism Embryos Exosomes Exosomes - metabolism Exosomes - physiology Fetuses Gene expression Gene Expression Regulation - genetics Gene sequencing Genes Glial fibrillary acidic protein Glioma Glioma - metabolism Glioma cells Growth factors Helix-loop-helix proteins (basic) Humans IL-1β Interleukin 6 Interleukin-6 - metabolism Medicine and Health Sciences Mesenchyme Metallothionein Metallothionein 3 Metastasis Morphology Nerve Tissue Proteins - metabolism Neural stem cells Neural Stem Cells - metabolism Neural Stem Cells - physiology Neurons - metabolism Neurosciences Notch1 protein Oncology Primary Cell Culture Proteins Rats Research and Analysis Methods Ribonucleic acid RNA Stat3 protein STAT3 Transcription Factor - metabolism Stem cell transplantation Stem cells Therapeutic applications Tumors |
| title | Glioma-derived exosomes drive the differentiation of neural stem cells to astrocytes |
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