JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models
Mismatches between pre-clinical and clinical results of stem cell therapeutics for ischemic stroke limit their clinical applicability. To overcome these discrepancies, precise planning of pre-clinical experiments that can be translated to clinical trials and the scientific elucidation of treatment m...
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Veröffentlicht in: | Aging (Albany, NY.) NY.), 2022-11, Vol.14 (22), p.8944-8969 |
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creator | Ha, Geun-Hyoung Kim, Eun Ji Park, Jee Soo Kim, Ji Eun Nam, Hyun Yeon, Je Young Lee, Sun-Ho Lee, Kyunghoon Kim, Chung Kwon Joo, Kyeung Min |
description | Mismatches between pre-clinical and clinical results of stem cell therapeutics for ischemic stroke limit their clinical applicability. To overcome these discrepancies, precise planning of pre-clinical experiments that can be translated to clinical trials and the scientific elucidation of treatment mechanisms is important. In this study, adult human neural stem cells (ahNSCs) derived from temporal lobe surgical samples were used (to avoid ethical and safety issues), and their therapeutic effects on ischemic stroke were examined using middle cerebral artery occlusion animal models. 5 × 10
ahNSCs was directly injected into the lateral ventricle of contralateral brain hemispheres of immune suppressed rat stroke models at the subacute phase of stroke. Compared with the mock-treated group, ahNSCs reduced brain tissue atrophy and neurological sensorimotor and memory functional loss. Tissue analysis demonstrated that the significant therapeutic effects were mediated by the neuroprotective and pro-angiogenic activities of ahNSCs, which preserved neurons in ischemic brain areas and decreased reactive astrogliosis and microglial activation. The neuroprotective and pro-angiogenic effects of ahNSCs were validated in
stroke models and were induced by paracrine factors excreted by ahNSCs. When the JAK2/STAT3 signaling pathway was inhibited by a specific inhibitor, AG490, the paracrine neuroprotective and pro-angiogenic effects of ahNSCs were reversed. This pre-clinical study that closely simulated clinical settings and provided treatment mechanisms of ahNSCs for ischemic stroke may aid the development of protocols for subsequent clinical trials of ahNSCs and the realization of clinically available stem cell therapeutics for ischemic stroke. |
doi_str_mv | 10.18632/aging.204410 |
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ahNSCs was directly injected into the lateral ventricle of contralateral brain hemispheres of immune suppressed rat stroke models at the subacute phase of stroke. Compared with the mock-treated group, ahNSCs reduced brain tissue atrophy and neurological sensorimotor and memory functional loss. Tissue analysis demonstrated that the significant therapeutic effects were mediated by the neuroprotective and pro-angiogenic activities of ahNSCs, which preserved neurons in ischemic brain areas and decreased reactive astrogliosis and microglial activation. The neuroprotective and pro-angiogenic effects of ahNSCs were validated in
stroke models and were induced by paracrine factors excreted by ahNSCs. When the JAK2/STAT3 signaling pathway was inhibited by a specific inhibitor, AG490, the paracrine neuroprotective and pro-angiogenic effects of ahNSCs were reversed. This pre-clinical study that closely simulated clinical settings and provided treatment mechanisms of ahNSCs for ischemic stroke may aid the development of protocols for subsequent clinical trials of ahNSCs and the realization of clinically available stem cell therapeutics for ischemic stroke.</description><identifier>ISSN: 1945-4589</identifier><identifier>EISSN: 1945-4589</identifier><identifier>DOI: 10.18632/aging.204410</identifier><identifier>PMID: 36446389</identifier><language>eng</language><publisher>United States: Impact Journals</publisher><subject>Angiogenesis Inducing Agents ; Animals ; Disease Models, Animal ; Humans ; Infarction, Middle Cerebral Artery - drug therapy ; Ischemic Stroke - therapy ; Janus Kinase 2 - metabolism ; Models, Animal ; Neural Stem Cells - metabolism ; Neuroprotective Agents - pharmacology ; Neuroprotective Agents - therapeutic use ; Rats ; Research Paper ; STAT3 Transcription Factor - metabolism ; Stroke - drug therapy</subject><ispartof>Aging (Albany, NY.), 2022-11, Vol.14 (22), p.8944-8969</ispartof><rights>Copyright: © 2022 Ha et al.</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c387t-2bf4b56f169f62255742ccf412a9f019cbfee2968f1c92856a04495dd307de503</citedby><cites>FETCH-LOGICAL-c387t-2bf4b56f169f62255742ccf412a9f019cbfee2968f1c92856a04495dd307de503</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740376/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9740376/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36446389$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ha, Geun-Hyoung</creatorcontrib><creatorcontrib>Kim, Eun Ji</creatorcontrib><creatorcontrib>Park, Jee Soo</creatorcontrib><creatorcontrib>Kim, Ji Eun</creatorcontrib><creatorcontrib>Nam, Hyun</creatorcontrib><creatorcontrib>Yeon, Je Young</creatorcontrib><creatorcontrib>Lee, Sun-Ho</creatorcontrib><creatorcontrib>Lee, Kyunghoon</creatorcontrib><creatorcontrib>Kim, Chung Kwon</creatorcontrib><creatorcontrib>Joo, Kyeung Min</creatorcontrib><title>JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models</title><title>Aging (Albany, NY.)</title><addtitle>Aging (Albany NY)</addtitle><description>Mismatches between pre-clinical and clinical results of stem cell therapeutics for ischemic stroke limit their clinical applicability. To overcome these discrepancies, precise planning of pre-clinical experiments that can be translated to clinical trials and the scientific elucidation of treatment mechanisms is important. In this study, adult human neural stem cells (ahNSCs) derived from temporal lobe surgical samples were used (to avoid ethical and safety issues), and their therapeutic effects on ischemic stroke were examined using middle cerebral artery occlusion animal models. 5 × 10
ahNSCs was directly injected into the lateral ventricle of contralateral brain hemispheres of immune suppressed rat stroke models at the subacute phase of stroke. Compared with the mock-treated group, ahNSCs reduced brain tissue atrophy and neurological sensorimotor and memory functional loss. Tissue analysis demonstrated that the significant therapeutic effects were mediated by the neuroprotective and pro-angiogenic activities of ahNSCs, which preserved neurons in ischemic brain areas and decreased reactive astrogliosis and microglial activation. The neuroprotective and pro-angiogenic effects of ahNSCs were validated in
stroke models and were induced by paracrine factors excreted by ahNSCs. When the JAK2/STAT3 signaling pathway was inhibited by a specific inhibitor, AG490, the paracrine neuroprotective and pro-angiogenic effects of ahNSCs were reversed. This pre-clinical study that closely simulated clinical settings and provided treatment mechanisms of ahNSCs for ischemic stroke may aid the development of protocols for subsequent clinical trials of ahNSCs and the realization of clinically available stem cell therapeutics for ischemic stroke.</description><subject>Angiogenesis Inducing Agents</subject><subject>Animals</subject><subject>Disease Models, Animal</subject><subject>Humans</subject><subject>Infarction, Middle Cerebral Artery - drug therapy</subject><subject>Ischemic Stroke - therapy</subject><subject>Janus Kinase 2 - metabolism</subject><subject>Models, Animal</subject><subject>Neural Stem Cells - metabolism</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Neuroprotective Agents - therapeutic use</subject><subject>Rats</subject><subject>Research Paper</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Stroke - drug therapy</subject><issn>1945-4589</issn><issn>1945-4589</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU1v1DAQhiMEoqVw5Ip85JLW34kvSKuqfFbiwHK2HGe8a0jsxXaK9i_xK_Hulqqc7NE8euedeZvmNcGXpJeMXpmND5tLijkn-ElzThQXLRe9evrof9a8yPkHxlIILp83Z0xyLlmvzps_n1df6NW39WrN0M6U7W-zRzOM3hTIKMCS4i7FArb4O0AmjKiWrQkbHzcQvEUlgSkzhILAuYplFB0y4zIVtF1mE44aZkK5wIwsTFNGPqDZj-MEtU4wHLomFUh7FK2dluxjqHiKPw8D_Vzbcxxhyi-bZ85MGV7dvxfN9_c36-uP7e3XD5-uV7etZX1XWjo4PgjpiFROUipEx6m1jhNqlMNE2cEBUCV7R6yivZCmnk6JcWS4G0FgdtG8O-nulqGewtblqke9S9VL2utovP6_E_xWb-KdVh3HrJNV4O29QIq_FshFzz4fdjcB4pI17TgTuNoiFW1PqE0x5wTuYQzB-pivPuarT_lW_s1jbw_0v0DZX78lprA</recordid><startdate>20221129</startdate><enddate>20221129</enddate><creator>Ha, Geun-Hyoung</creator><creator>Kim, Eun Ji</creator><creator>Park, Jee Soo</creator><creator>Kim, Ji Eun</creator><creator>Nam, Hyun</creator><creator>Yeon, Je Young</creator><creator>Lee, Sun-Ho</creator><creator>Lee, Kyunghoon</creator><creator>Kim, Chung Kwon</creator><creator>Joo, Kyeung Min</creator><general>Impact Journals</general><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20221129</creationdate><title>JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models</title><author>Ha, Geun-Hyoung ; Kim, Eun Ji ; Park, Jee Soo ; Kim, Ji Eun ; Nam, Hyun ; Yeon, Je Young ; Lee, Sun-Ho ; Lee, Kyunghoon ; Kim, Chung Kwon ; Joo, Kyeung Min</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c387t-2bf4b56f169f62255742ccf412a9f019cbfee2968f1c92856a04495dd307de503</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Angiogenesis Inducing Agents</topic><topic>Animals</topic><topic>Disease Models, Animal</topic><topic>Humans</topic><topic>Infarction, Middle Cerebral Artery - drug therapy</topic><topic>Ischemic Stroke - therapy</topic><topic>Janus Kinase 2 - metabolism</topic><topic>Models, Animal</topic><topic>Neural Stem Cells - metabolism</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>Neuroprotective Agents - therapeutic use</topic><topic>Rats</topic><topic>Research Paper</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Stroke - drug therapy</topic><toplevel>online_resources</toplevel><creatorcontrib>Ha, Geun-Hyoung</creatorcontrib><creatorcontrib>Kim, Eun Ji</creatorcontrib><creatorcontrib>Park, Jee Soo</creatorcontrib><creatorcontrib>Kim, Ji Eun</creatorcontrib><creatorcontrib>Nam, Hyun</creatorcontrib><creatorcontrib>Yeon, Je Young</creatorcontrib><creatorcontrib>Lee, Sun-Ho</creatorcontrib><creatorcontrib>Lee, Kyunghoon</creatorcontrib><creatorcontrib>Kim, Chung Kwon</creatorcontrib><creatorcontrib>Joo, Kyeung Min</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Aging (Albany, NY.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ha, Geun-Hyoung</au><au>Kim, Eun Ji</au><au>Park, Jee Soo</au><au>Kim, Ji Eun</au><au>Nam, Hyun</au><au>Yeon, Je Young</au><au>Lee, Sun-Ho</au><au>Lee, Kyunghoon</au><au>Kim, Chung Kwon</au><au>Joo, Kyeung Min</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models</atitle><jtitle>Aging (Albany, NY.)</jtitle><addtitle>Aging (Albany NY)</addtitle><date>2022-11-29</date><risdate>2022</risdate><volume>14</volume><issue>22</issue><spage>8944</spage><epage>8969</epage><pages>8944-8969</pages><issn>1945-4589</issn><eissn>1945-4589</eissn><abstract>Mismatches between pre-clinical and clinical results of stem cell therapeutics for ischemic stroke limit their clinical applicability. To overcome these discrepancies, precise planning of pre-clinical experiments that can be translated to clinical trials and the scientific elucidation of treatment mechanisms is important. In this study, adult human neural stem cells (ahNSCs) derived from temporal lobe surgical samples were used (to avoid ethical and safety issues), and their therapeutic effects on ischemic stroke were examined using middle cerebral artery occlusion animal models. 5 × 10
ahNSCs was directly injected into the lateral ventricle of contralateral brain hemispheres of immune suppressed rat stroke models at the subacute phase of stroke. Compared with the mock-treated group, ahNSCs reduced brain tissue atrophy and neurological sensorimotor and memory functional loss. Tissue analysis demonstrated that the significant therapeutic effects were mediated by the neuroprotective and pro-angiogenic activities of ahNSCs, which preserved neurons in ischemic brain areas and decreased reactive astrogliosis and microglial activation. The neuroprotective and pro-angiogenic effects of ahNSCs were validated in
stroke models and were induced by paracrine factors excreted by ahNSCs. When the JAK2/STAT3 signaling pathway was inhibited by a specific inhibitor, AG490, the paracrine neuroprotective and pro-angiogenic effects of ahNSCs were reversed. This pre-clinical study that closely simulated clinical settings and provided treatment mechanisms of ahNSCs for ischemic stroke may aid the development of protocols for subsequent clinical trials of ahNSCs and the realization of clinically available stem cell therapeutics for ischemic stroke.</abstract><cop>United States</cop><pub>Impact Journals</pub><pmid>36446389</pmid><doi>10.18632/aging.204410</doi><tpages>26</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Angiogenesis Inducing Agents Animals Disease Models, Animal Humans Infarction, Middle Cerebral Artery - drug therapy Ischemic Stroke - therapy Janus Kinase 2 - metabolism Models, Animal Neural Stem Cells - metabolism Neuroprotective Agents - pharmacology Neuroprotective Agents - therapeutic use Rats Research Paper STAT3 Transcription Factor - metabolism Stroke - drug therapy |
title | JAK2/STAT3 pathway mediates neuroprotective and pro-angiogenic treatment effects of adult human neural stem cells in middle cerebral artery occlusion stroke animal models |
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