IFNγ-stimulated dendritic cell extracellular vesicles can be nasally administered to the brain and enter oligodendrocytes
Extracellular vesicles secreted from IFNγ-stimulated rat dendritic cells (referred to here as IFNγ-DC-EVs) contain miRNAs which promote myelination (including but not limited to miR-219), and preferentially enter oligodendrocytes in brain slice cultures. IFNγ-DC-EVs also increase myelination when na...
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| description | Extracellular vesicles secreted from IFNγ-stimulated rat dendritic cells (referred to here as IFNγ-DC-EVs) contain miRNAs which promote myelination (including but not limited to miR-219), and preferentially enter oligodendrocytes in brain slice cultures. IFNγ-DC-EVs also increase myelination when nasally administered to naïve rats. While we can infer that these extracellular vesicles enter the CNS from functional studies, here we demonstrate biodistribution throughout the brain after nasal delivery by way of imaging studies. After nasal administration, Xenolight DiR-labelled IFNγ-DC-EVs were detected 30 minutes later throughout the brain and the cervical spinal cord. We next examined cellular uptake of IFNγ-DC-EVs by transfecting IFNγ-DC-EVs with mCherry mRNA prior to nasal administration. mCherry-positive cells were found along the rostrocaudal axis of the brain to the brainstem. These cells morphologically resembled oligodendrocytes, and indeed cell-specific co-staining for neurons, astrocytes, microglia and oligodendrocytes showed that mcherry positive cells were predominantly oligodendrocytes. This is in keeping with our prior
in vitro
results showing that IFNγ-DC-EVs are preferentially taken up by oligodendrocytes, and to a lesser extent, microglia. To confirm that IFNγ-DC-EVs delivered cargo to oligodendrocytes, we quantified protein levels of miR-219 mRNA targets expressed in oligodendrocyte lineage cells, and found significantly reduced expression. Finally, we compared intranasal versus intravenous delivery of Xenolight DiR-labelled IFNγ-DC-EVs. Though labelled IFNγ-DC-EVs entered the CNS via both routes, we found that nasal delivery more specifically targeted the CNS with less accumulation in the liver. Taken together, these data show that intranasal administration is an effective route for delivery of IFNγ-DC-EVs to the CNS, and provides additional support for their development as an EV-based neurotherapeutic that, for the first time, targets oligodendrocytes. |
| doi_str_mv | 10.1371/journal.pone.0255778 |
| format | Article |
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in vitro
results showing that IFNγ-DC-EVs are preferentially taken up by oligodendrocytes, and to a lesser extent, microglia. To confirm that IFNγ-DC-EVs delivered cargo to oligodendrocytes, we quantified protein levels of miR-219 mRNA targets expressed in oligodendrocyte lineage cells, and found significantly reduced expression. Finally, we compared intranasal versus intravenous delivery of Xenolight DiR-labelled IFNγ-DC-EVs. Though labelled IFNγ-DC-EVs entered the CNS via both routes, we found that nasal delivery more specifically targeted the CNS with less accumulation in the liver. Taken together, these data show that intranasal administration is an effective route for delivery of IFNγ-DC-EVs to the CNS, and provides additional support for their development as an EV-based neurotherapeutic that, for the first time, targets oligodendrocytes.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0255778</identifier><identifier>PMID: 34388189</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Astrocytes ; Biology and Life Sciences ; Bone marrow ; Brain ; Brain slice preparation ; Brain stem ; Dendritic cells ; Extracellular vesicles ; Funding ; Intranasal administration ; Intravenous administration ; Laboratory animals ; Medicine and Health Sciences ; Microglia ; MicroRNAs ; mRNA ; Myelination ; Neuroimaging ; Neurology ; Oligodendrocytes ; Oxidative stress ; Proteins ; Research and Analysis Methods ; Respiration ; Spinal cord ; Vesicles ; γ-Interferon</subject><ispartof>PloS one, 2021-08, Vol.16 (8), p.e0255778-e0255778</ispartof><rights>2021 Pusic 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>2021 Pusic et al 2021 Pusic et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c503t-6041209d28aa3e26244a3f22656adff1f6dea49c7120a5c66a6bfdff37a620433</citedby><cites>FETCH-LOGICAL-c503t-6041209d28aa3e26244a3f22656adff1f6dea49c7120a5c66a6bfdff37a620433</cites><orcidid>0000-0003-4861-0230</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/PMC8363003/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363003/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids></links><search><contributor>de Castro, Fernando</contributor><creatorcontrib>Pusic, Kae M.</creatorcontrib><creatorcontrib>Kraig, Richard P.</creatorcontrib><creatorcontrib>Pusic, Aya D.</creatorcontrib><title>IFNγ-stimulated dendritic cell extracellular vesicles can be nasally administered to the brain and enter oligodendrocytes</title><title>PloS one</title><description>Extracellular vesicles secreted from IFNγ-stimulated rat dendritic cells (referred to here as IFNγ-DC-EVs) contain miRNAs which promote myelination (including but not limited to miR-219), and preferentially enter oligodendrocytes in brain slice cultures. IFNγ-DC-EVs also increase myelination when nasally administered to naïve rats. While we can infer that these extracellular vesicles enter the CNS from functional studies, here we demonstrate biodistribution throughout the brain after nasal delivery by way of imaging studies. After nasal administration, Xenolight DiR-labelled IFNγ-DC-EVs were detected 30 minutes later throughout the brain and the cervical spinal cord. We next examined cellular uptake of IFNγ-DC-EVs by transfecting IFNγ-DC-EVs with mCherry mRNA prior to nasal administration. mCherry-positive cells were found along the rostrocaudal axis of the brain to the brainstem. These cells morphologically resembled oligodendrocytes, and indeed cell-specific co-staining for neurons, astrocytes, microglia and oligodendrocytes showed that mcherry positive cells were predominantly oligodendrocytes. This is in keeping with our prior
in vitro
results showing that IFNγ-DC-EVs are preferentially taken up by oligodendrocytes, and to a lesser extent, microglia. To confirm that IFNγ-DC-EVs delivered cargo to oligodendrocytes, we quantified protein levels of miR-219 mRNA targets expressed in oligodendrocyte lineage cells, and found significantly reduced expression. Finally, we compared intranasal versus intravenous delivery of Xenolight DiR-labelled IFNγ-DC-EVs. Though labelled IFNγ-DC-EVs entered the CNS via both routes, we found that nasal delivery more specifically targeted the CNS with less accumulation in the liver. Taken together, these data show that intranasal administration is an effective route for delivery of IFNγ-DC-EVs to the CNS, and provides additional support for their development as an EV-based neurotherapeutic that, for the first time, targets oligodendrocytes.</description><subject>Astrocytes</subject><subject>Biology and Life Sciences</subject><subject>Bone marrow</subject><subject>Brain</subject><subject>Brain slice preparation</subject><subject>Brain stem</subject><subject>Dendritic cells</subject><subject>Extracellular vesicles</subject><subject>Funding</subject><subject>Intranasal administration</subject><subject>Intravenous administration</subject><subject>Laboratory animals</subject><subject>Medicine and Health Sciences</subject><subject>Microglia</subject><subject>MicroRNAs</subject><subject>mRNA</subject><subject>Myelination</subject><subject>Neuroimaging</subject><subject>Neurology</subject><subject>Oligodendrocytes</subject><subject>Oxidative 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dendritic cell extracellular vesicles can be nasally administered to the brain and enter oligodendrocytes</title><author>Pusic, Kae M. ; Kraig, Richard P. ; Pusic, Aya D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c503t-6041209d28aa3e26244a3f22656adff1f6dea49c7120a5c66a6bfdff37a620433</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Astrocytes</topic><topic>Biology and Life Sciences</topic><topic>Bone marrow</topic><topic>Brain</topic><topic>Brain slice preparation</topic><topic>Brain stem</topic><topic>Dendritic cells</topic><topic>Extracellular vesicles</topic><topic>Funding</topic><topic>Intranasal administration</topic><topic>Intravenous administration</topic><topic>Laboratory animals</topic><topic>Medicine and Health 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pusic, Kae M.</au><au>Kraig, Richard P.</au><au>Pusic, Aya D.</au><au>de Castro, Fernando</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IFNγ-stimulated dendritic cell extracellular vesicles can be nasally administered to the brain and enter oligodendrocytes</atitle><jtitle>PloS one</jtitle><date>2021-08-01</date><risdate>2021</risdate><volume>16</volume><issue>8</issue><spage>e0255778</spage><epage>e0255778</epage><pages>e0255778-e0255778</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Extracellular vesicles secreted from IFNγ-stimulated rat dendritic cells (referred to here as IFNγ-DC-EVs) contain miRNAs which promote myelination (including but not limited to miR-219), and preferentially enter oligodendrocytes in brain slice cultures. IFNγ-DC-EVs also increase myelination when nasally administered to naïve rats. While we can infer that these extracellular vesicles enter the CNS from functional studies, here we demonstrate biodistribution throughout the brain after nasal delivery by way of imaging studies. After nasal administration, Xenolight DiR-labelled IFNγ-DC-EVs were detected 30 minutes later throughout the brain and the cervical spinal cord. We next examined cellular uptake of IFNγ-DC-EVs by transfecting IFNγ-DC-EVs with mCherry mRNA prior to nasal administration. mCherry-positive cells were found along the rostrocaudal axis of the brain to the brainstem. These cells morphologically resembled oligodendrocytes, and indeed cell-specific co-staining for neurons, astrocytes, microglia and oligodendrocytes showed that mcherry positive cells were predominantly oligodendrocytes. This is in keeping with our prior
in vitro
results showing that IFNγ-DC-EVs are preferentially taken up by oligodendrocytes, and to a lesser extent, microglia. To confirm that IFNγ-DC-EVs delivered cargo to oligodendrocytes, we quantified protein levels of miR-219 mRNA targets expressed in oligodendrocyte lineage cells, and found significantly reduced expression. Finally, we compared intranasal versus intravenous delivery of Xenolight DiR-labelled IFNγ-DC-EVs. Though labelled IFNγ-DC-EVs entered the CNS via both routes, we found that nasal delivery more specifically targeted the CNS with less accumulation in the liver. Taken together, these data show that intranasal administration is an effective route for delivery of IFNγ-DC-EVs to the CNS, and provides additional support for their development as an EV-based neurotherapeutic that, for the first time, targets oligodendrocytes.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>34388189</pmid><doi>10.1371/journal.pone.0255778</doi><orcidid>https://orcid.org/0000-0003-4861-0230</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Astrocytes Biology and Life Sciences Bone marrow Brain Brain slice preparation Brain stem Dendritic cells Extracellular vesicles Funding Intranasal administration Intravenous administration Laboratory animals Medicine and Health Sciences Microglia MicroRNAs mRNA Myelination Neuroimaging Neurology Oligodendrocytes Oxidative stress Proteins Research and Analysis Methods Respiration Spinal cord Vesicles γ-Interferon |
| title | IFNγ-stimulated dendritic cell extracellular vesicles can be nasally administered to the brain and enter oligodendrocytes |
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