Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury
Background/Aims: Neurotoxic A1 astrocytes are induced by inflammation after spinal cord injury (SCI), and the inflammation-related Nuclear Factor Kappa B (NFκB) pathway may be related to A1-astrocyte activation. Mesenchymal stem cell (MSC) transplantation is a promising therapy for SCI, where transp...
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| Veröffentlicht in: | Cellular physiology and biochemistry 2018-01, Vol.50 (4), p.1535-1559 |
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| creator | Wang, Lin Pei, Shuang Han, Linlin Guo, Bin Li, Yanfei Duan, Ranran Yao, Yaobing Xue, Bohan Chen, Xuemei Jia, Yanjie |
| description | Background/Aims: Neurotoxic A1 astrocytes are induced by inflammation after spinal cord injury (SCI), and the inflammation-related Nuclear Factor Kappa B (NFκB) pathway may be related to A1-astrocyte activation. Mesenchymal stem cell (MSC) transplantation is a promising therapy for SCI, where transplanted MSCs exhibit anti-inflammatory effects by downregulating proinflammatory factors, such as Tumor Necrosis Factor (TNF)-α and NFκB. MSC-exosomes (MSC-exo) reportedly mimic the beneficial effects of MSCs. Therefore, in this study, we investigated whether MSCs and MSC-exo exert inhibitory effects on A1 astrocytes and are beneficial for recovery after SCI. Methods: The effects of MSC and MSC-exo on SCIinduced A1 astrocytes, and the potential mechanisms were investigated in vitro and in vivo using immunofluorescence and western blot. In addition, we assessed the histopathology, levels of proinflammatory cytokines and locomotor function to verify the effects of MSC and MSC-exo on SCI rats. Results: MSC or MSC-exo co-culture reduced the proportion of SCIinduced A1 astrocytes. Intravenously-injected MSC or MSC-exo after SCI significantly reduced the proportion of A1 astrocytes, the percentage of p65 positive nuclei in astrocytes, and the percentage of TUNEL-positive cells in the ventral horn. Additionally, we observed decreased lesion area and expression of TNFα, Interleukin (IL)-1α and IL-1β, elevated expression of Myelin Basic Protein (MBP), Synaptophysin (Syn) and Neuronal Nuclei (NeuN), and improved Basso, Beattie & Bresnahan (BBB) scores and inclined-plane-test angle. In vitro assay showed that MSC and MSC-exo reduced SCI-induced A1 astrocytes, probably via inhibiting the nuclear translocation of the NFκB p65. Conclusion: MSC and MSC-exo reduce SCI-induced A1 astrocytes, probably via inhibiting nuclear translocation of NFκB p65, and exert antiinflammatory and neuroprotective effects following SCI, with the therapeutic effect of MSCexo comparable with that of MSCs when applied intravenously. |
| doi_str_mv | 10.1159/000494652 |
| format | Article |
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Mesenchymal stem cell (MSC) transplantation is a promising therapy for SCI, where transplanted MSCs exhibit anti-inflammatory effects by downregulating proinflammatory factors, such as Tumor Necrosis Factor (TNF)-α and NFκB. MSC-exosomes (MSC-exo) reportedly mimic the beneficial effects of MSCs. Therefore, in this study, we investigated whether MSCs and MSC-exo exert inhibitory effects on A1 astrocytes and are beneficial for recovery after SCI. Methods: The effects of MSC and MSC-exo on SCIinduced A1 astrocytes, and the potential mechanisms were investigated in vitro and in vivo using immunofluorescence and western blot. In addition, we assessed the histopathology, levels of proinflammatory cytokines and locomotor function to verify the effects of MSC and MSC-exo on SCI rats. Results: MSC or MSC-exo co-culture reduced the proportion of SCIinduced A1 astrocytes. Intravenously-injected MSC or MSC-exo after SCI significantly reduced the proportion of A1 astrocytes, the percentage of p65 positive nuclei in astrocytes, and the percentage of TUNEL-positive cells in the ventral horn. Additionally, we observed decreased lesion area and expression of TNFα, Interleukin (IL)-1α and IL-1β, elevated expression of Myelin Basic Protein (MBP), Synaptophysin (Syn) and Neuronal Nuclei (NeuN), and improved Basso, Beattie & Bresnahan (BBB) scores and inclined-plane-test angle. In vitro assay showed that MSC and MSC-exo reduced SCI-induced A1 astrocytes, probably via inhibiting the nuclear translocation of the NFκB p65. Conclusion: MSC and MSC-exo reduce SCI-induced A1 astrocytes, probably via inhibiting nuclear translocation of NFκB p65, and exert antiinflammatory and neuroprotective effects following SCI, with the therapeutic effect of MSCexo comparable with that of MSCs when applied intravenously.</description><identifier>ISSN: 1015-8987</identifier><identifier>EISSN: 1421-9778</identifier><identifier>DOI: 10.1159/000494652</identifier><identifier>PMID: 30376671</identifier><language>eng</language><publisher>Basel, Switzerland: S. Karger AG</publisher><subject>Animals ; Astrocytes ; Astrocytes - cytology ; Astrocytes - metabolism ; Bone marrow ; Cells, Cultured ; Cytokines ; Cytokines - metabolism ; Down-Regulation ; Exosomes ; Exosomes - chemistry ; Exosomes - metabolism ; Exosomes - transplantation ; Experiments ; Flow cytometry ; Fluorescent Dyes - chemistry ; I-kappa B Kinase - metabolism ; Inflammation ; Ischemia ; Locomotion ; Male ; Mesenchymal stem cell ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells - chemistry ; Mesenchymal Stem Cells - cytology ; Mesenchymal Stem Cells - metabolism ; Microscopy, Fluorescence ; Morphology ; Myelin Basic Protein - metabolism ; Nervous system ; Original Paper ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Recovery of Function ; Spinal cord injuries ; Spinal Cord Injuries - metabolism ; Spinal Cord Injuries - pathology ; Spinal Cord Injuries - veterinary ; Spinal cord injury ; Stem cells ; Transcription Factor RelA - metabolism ; Traumatic brain injury</subject><ispartof>Cellular physiology and biochemistry, 2018-01, Vol.50 (4), p.1535-1559</ispartof><rights>2018 The Author(s). Published by S. Karger AG, Basel</rights><rights>2018 The Author(s). Published by S. Karger AG, Basel.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-29bfd8af88c70b546646755a58e8aab1f6c806d37f5bfd8cf4244ac0436f543b3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,865,2103,27639,27928,27929</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30376671$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Lin</creatorcontrib><creatorcontrib>Pei, Shuang</creatorcontrib><creatorcontrib>Han, Linlin</creatorcontrib><creatorcontrib>Guo, Bin</creatorcontrib><creatorcontrib>Li, Yanfei</creatorcontrib><creatorcontrib>Duan, Ranran</creatorcontrib><creatorcontrib>Yao, Yaobing</creatorcontrib><creatorcontrib>Xue, Bohan</creatorcontrib><creatorcontrib>Chen, Xuemei</creatorcontrib><creatorcontrib>Jia, Yanjie</creatorcontrib><title>Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury</title><title>Cellular physiology and biochemistry</title><addtitle>Cell Physiol Biochem</addtitle><description>Background/Aims: Neurotoxic A1 astrocytes are induced by inflammation after spinal cord injury (SCI), and the inflammation-related Nuclear Factor Kappa B (NFκB) pathway may be related to A1-astrocyte activation. Mesenchymal stem cell (MSC) transplantation is a promising therapy for SCI, where transplanted MSCs exhibit anti-inflammatory effects by downregulating proinflammatory factors, such as Tumor Necrosis Factor (TNF)-α and NFκB. MSC-exosomes (MSC-exo) reportedly mimic the beneficial effects of MSCs. Therefore, in this study, we investigated whether MSCs and MSC-exo exert inhibitory effects on A1 astrocytes and are beneficial for recovery after SCI. Methods: The effects of MSC and MSC-exo on SCIinduced A1 astrocytes, and the potential mechanisms were investigated in vitro and in vivo using immunofluorescence and western blot. In addition, we assessed the histopathology, levels of proinflammatory cytokines and locomotor function to verify the effects of MSC and MSC-exo on SCI rats. Results: MSC or MSC-exo co-culture reduced the proportion of SCIinduced A1 astrocytes. Intravenously-injected MSC or MSC-exo after SCI significantly reduced the proportion of A1 astrocytes, the percentage of p65 positive nuclei in astrocytes, and the percentage of TUNEL-positive cells in the ventral horn. Additionally, we observed decreased lesion area and expression of TNFα, Interleukin (IL)-1α and IL-1β, elevated expression of Myelin Basic Protein (MBP), Synaptophysin (Syn) and Neuronal Nuclei (NeuN), and improved Basso, Beattie & Bresnahan (BBB) scores and inclined-plane-test angle. In vitro assay showed that MSC and MSC-exo reduced SCI-induced A1 astrocytes, probably via inhibiting the nuclear translocation of the NFκB p65. Conclusion: MSC and MSC-exo reduce SCI-induced A1 astrocytes, probably via inhibiting nuclear translocation of NFκB p65, and exert antiinflammatory and neuroprotective effects following SCI, with the therapeutic effect of MSCexo comparable with that of MSCs when applied intravenously.</description><subject>Animals</subject><subject>Astrocytes</subject><subject>Astrocytes - cytology</subject><subject>Astrocytes - metabolism</subject><subject>Bone marrow</subject><subject>Cells, Cultured</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Down-Regulation</subject><subject>Exosomes</subject><subject>Exosomes - chemistry</subject><subject>Exosomes - metabolism</subject><subject>Exosomes - transplantation</subject><subject>Experiments</subject><subject>Flow cytometry</subject><subject>Fluorescent Dyes - chemistry</subject><subject>I-kappa B Kinase - metabolism</subject><subject>Inflammation</subject><subject>Ischemia</subject><subject>Locomotion</subject><subject>Male</subject><subject>Mesenchymal stem cell</subject><subject>Mesenchymal Stem Cell Transplantation</subject><subject>Mesenchymal Stem Cells - chemistry</subject><subject>Mesenchymal Stem Cells - cytology</subject><subject>Mesenchymal Stem Cells - metabolism</subject><subject>Microscopy, Fluorescence</subject><subject>Morphology</subject><subject>Myelin Basic Protein - metabolism</subject><subject>Nervous system</subject><subject>Original Paper</subject><subject>Phosphorylation</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Recovery of Function</subject><subject>Spinal cord injuries</subject><subject>Spinal Cord Injuries - metabolism</subject><subject>Spinal Cord Injuries - pathology</subject><subject>Spinal Cord Injuries - veterinary</subject><subject>Spinal cord injury</subject><subject>Stem cells</subject><subject>Transcription Factor RelA - metabolism</subject><subject>Traumatic brain injury</subject><issn>1015-8987</issn><issn>1421-9778</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>M--</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DOA</sourceid><recordid>eNptkc1u1DAURiMEoqWwYI-QJVYsAv63s5ymLYxUYMTA2nIceyZDEgc7aZs34Jl4CJ4JlxmGDSvbn47Op-ubZc8RfIMQK95CCGlBOcMPslNEMcoLIeTDdIeI5bKQ4iR7EuMOpqco8OPshEAiOBfoNPvxwUbbm-3c6RasR9uB0rZtfmFDc2NrcHnno-9sBJ9tPRkLFggs4hi8mccU3jQaXPjbPtjN1Oqx8T3wDqy2Pg5bH-YUJcXHq18_z8GKM7CeqqlvRtD0YD00fSosfajBst9NYX6aPXK6jfbZ4TzLvl5dfinf59ef3i3LxXVuKCdjjovK1VI7KY2AFaOcUy4Y00xaqXWFHDcS8poIx-5B4yimVBtICXeMkoqcZcu9t_Z6p4bQdDrMyutG_Ql82Cgdxsa0VtUOM2IsIw7W1FSFxFWBkCFV-kQEqUiuV3vXEPz3ycZR7fwU0mBRYQKRLKjAOFGv95QJPsZg3bEVQXW_P3XcX2JfHoxT1dn6SP5d2L_KbzpsbDgC5ep8r1BD7RL14r_UoeU3hq2qXg</recordid><startdate>20180101</startdate><enddate>20180101</enddate><creator>Wang, Lin</creator><creator>Pei, Shuang</creator><creator>Han, Linlin</creator><creator>Guo, Bin</creator><creator>Li, Yanfei</creator><creator>Duan, Ranran</creator><creator>Yao, Yaobing</creator><creator>Xue, Bohan</creator><creator>Chen, Xuemei</creator><creator>Jia, Yanjie</creator><general>S. Karger AG</general><general>Cell Physiol Biochem Press GmbH & Co KG</general><scope>M--</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>DOA</scope></search><sort><creationdate>20180101</creationdate><title>Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury</title><author>Wang, Lin ; Pei, Shuang ; Han, Linlin ; Guo, Bin ; Li, Yanfei ; Duan, Ranran ; Yao, Yaobing ; Xue, Bohan ; Chen, Xuemei ; Jia, Yanjie</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-29bfd8af88c70b546646755a58e8aab1f6c806d37f5bfd8cf4244ac0436f543b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Astrocytes</topic><topic>Astrocytes - cytology</topic><topic>Astrocytes - metabolism</topic><topic>Bone marrow</topic><topic>Cells, Cultured</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>Down-Regulation</topic><topic>Exosomes</topic><topic>Exosomes - chemistry</topic><topic>Exosomes - metabolism</topic><topic>Exosomes - transplantation</topic><topic>Experiments</topic><topic>Flow cytometry</topic><topic>Fluorescent Dyes - chemistry</topic><topic>I-kappa B Kinase - metabolism</topic><topic>Inflammation</topic><topic>Ischemia</topic><topic>Locomotion</topic><topic>Male</topic><topic>Mesenchymal stem cell</topic><topic>Mesenchymal Stem Cell Transplantation</topic><topic>Mesenchymal Stem Cells - chemistry</topic><topic>Mesenchymal Stem Cells - cytology</topic><topic>Mesenchymal Stem Cells - metabolism</topic><topic>Microscopy, Fluorescence</topic><topic>Morphology</topic><topic>Myelin Basic Protein - metabolism</topic><topic>Nervous system</topic><topic>Original Paper</topic><topic>Phosphorylation</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Recovery of Function</topic><topic>Spinal cord injuries</topic><topic>Spinal Cord Injuries - metabolism</topic><topic>Spinal Cord Injuries - pathology</topic><topic>Spinal Cord Injuries - veterinary</topic><topic>Spinal cord injury</topic><topic>Stem cells</topic><topic>Transcription Factor RelA - metabolism</topic><topic>Traumatic brain injury</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Lin</creatorcontrib><creatorcontrib>Pei, Shuang</creatorcontrib><creatorcontrib>Han, Linlin</creatorcontrib><creatorcontrib>Guo, Bin</creatorcontrib><creatorcontrib>Li, Yanfei</creatorcontrib><creatorcontrib>Duan, Ranran</creatorcontrib><creatorcontrib>Yao, Yaobing</creatorcontrib><creatorcontrib>Xue, Bohan</creatorcontrib><creatorcontrib>Chen, Xuemei</creatorcontrib><creatorcontrib>Jia, Yanjie</creatorcontrib><collection>Karger Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Cellular physiology and biochemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Lin</au><au>Pei, Shuang</au><au>Han, Linlin</au><au>Guo, Bin</au><au>Li, Yanfei</au><au>Duan, Ranran</au><au>Yao, Yaobing</au><au>Xue, Bohan</au><au>Chen, Xuemei</au><au>Jia, Yanjie</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury</atitle><jtitle>Cellular physiology and biochemistry</jtitle><addtitle>Cell Physiol Biochem</addtitle><date>2018-01-01</date><risdate>2018</risdate><volume>50</volume><issue>4</issue><spage>1535</spage><epage>1559</epage><pages>1535-1559</pages><issn>1015-8987</issn><eissn>1421-9778</eissn><abstract>Background/Aims: Neurotoxic A1 astrocytes are induced by inflammation after spinal cord injury (SCI), and the inflammation-related Nuclear Factor Kappa B (NFκB) pathway may be related to A1-astrocyte activation. Mesenchymal stem cell (MSC) transplantation is a promising therapy for SCI, where transplanted MSCs exhibit anti-inflammatory effects by downregulating proinflammatory factors, such as Tumor Necrosis Factor (TNF)-α and NFκB. MSC-exosomes (MSC-exo) reportedly mimic the beneficial effects of MSCs. Therefore, in this study, we investigated whether MSCs and MSC-exo exert inhibitory effects on A1 astrocytes and are beneficial for recovery after SCI. Methods: The effects of MSC and MSC-exo on SCIinduced A1 astrocytes, and the potential mechanisms were investigated in vitro and in vivo using immunofluorescence and western blot. In addition, we assessed the histopathology, levels of proinflammatory cytokines and locomotor function to verify the effects of MSC and MSC-exo on SCI rats. Results: MSC or MSC-exo co-culture reduced the proportion of SCIinduced A1 astrocytes. Intravenously-injected MSC or MSC-exo after SCI significantly reduced the proportion of A1 astrocytes, the percentage of p65 positive nuclei in astrocytes, and the percentage of TUNEL-positive cells in the ventral horn. Additionally, we observed decreased lesion area and expression of TNFα, Interleukin (IL)-1α and IL-1β, elevated expression of Myelin Basic Protein (MBP), Synaptophysin (Syn) and Neuronal Nuclei (NeuN), and improved Basso, Beattie & Bresnahan (BBB) scores and inclined-plane-test angle. In vitro assay showed that MSC and MSC-exo reduced SCI-induced A1 astrocytes, probably via inhibiting the nuclear translocation of the NFκB p65. Conclusion: MSC and MSC-exo reduce SCI-induced A1 astrocytes, probably via inhibiting nuclear translocation of NFκB p65, and exert antiinflammatory and neuroprotective effects following SCI, with the therapeutic effect of MSCexo comparable with that of MSCs when applied intravenously.</abstract><cop>Basel, Switzerland</cop><pub>S. Karger AG</pub><pmid>30376671</pmid><doi>10.1159/000494652</doi><tpages>25</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Astrocytes Astrocytes - cytology Astrocytes - metabolism Bone marrow Cells, Cultured Cytokines Cytokines - metabolism Down-Regulation Exosomes Exosomes - chemistry Exosomes - metabolism Exosomes - transplantation Experiments Flow cytometry Fluorescent Dyes - chemistry I-kappa B Kinase - metabolism Inflammation Ischemia Locomotion Male Mesenchymal stem cell Mesenchymal Stem Cell Transplantation Mesenchymal Stem Cells - chemistry Mesenchymal Stem Cells - cytology Mesenchymal Stem Cells - metabolism Microscopy, Fluorescence Morphology Myelin Basic Protein - metabolism Nervous system Original Paper Phosphorylation Rats Rats, Sprague-Dawley Recovery of Function Spinal cord injuries Spinal Cord Injuries - metabolism Spinal Cord Injuries - pathology Spinal Cord Injuries - veterinary Spinal cord injury Stem cells Transcription Factor RelA - metabolism Traumatic brain injury |
| title | Mesenchymal Stem Cell-Derived Exosomes Reduce A1 Astrocytes via Downregulation of Phosphorylated NFκB P65 Subunit in Spinal Cord Injury |
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