Implantation Site and Lesion Topology Determine Efficacy of a Human Neural Stem Cell Line in a Rat Model of Chronic Stroke
Identifieur interne : 001976 ( Istex/Corpus ); précédent : 001975; suivant : 001977Implantation Site and Lesion Topology Determine Efficacy of a Human Neural Stem Cell Line in a Rat Model of Chronic Stroke
Auteurs : Edward J. Smith ; R. Paul Stroemer ; Natalia Gorenkova ; Mitsuko Nakajima ; William R. Crum ; Ellen Tang ; Lara Stevanato ; John D. Sinden ; Michel ModoSource :
- STEM CELLS [ 1066-5099 ] ; 2012-04.
English descriptors
Abstract
Stroke remains one of the most promising targets for cell therapy. Thorough preclinical efficacy testing of human neural stem cell (hNSC) lines in a rat model of stroke (transient middle cerebral artery occlusion) is, however, required for translation into a clinical setting. Magnetic resonance imaging (MRI) here confirmed stroke damage and allowed the targeted injection of 450,000 hNSCs (CTX0E03) into peri‐infarct tissue, rather than the lesion cyst. Intraparenchymal cell implants improved sensorimotor dysfunctions (bilateral asymmetry test) and motor deficits (footfault test and rotameter). Importantly, analyses based on lesion topology (striatal vs. striatal + cortical damage) revealed a more significant improvement in animals with a stroke confined to the striatum. However, no improvement in learning and memory (water maze) was evident. An intracerebroventricular injection of cells did not result in any improvement. MRI‐based lesion, striatal and cortical volumes were unchanged in treated animals compared to those with stroke that received an intraparenchymal injection of suspension vehicle. Grafted cells only survived after intraparenchymal injection with a striatal + cortical topology resulting in better graft survival (16,026 cells) than in animals with smaller striatal lesions (2,374 cells). Almost 20% of cells differentiated into glial fibrillary acidic protein+ astrocytes, but <2% turned into FOX3+ neurons. These results indicate that CTX0E03 implants robustly recover behavioral dysfunction over a 3‐month time frame and that this effect is specific to their site of implantation. Lesion topology is potentially an important factor in the recovery, with a stroke confined to the striatum showing a better outcome compared to a larger area of damage. STEM CELLS 2012; 30:785–796
Url:
DOI: 10.1002/stem.1024
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ISTEX:01782887DB1C4CEFD9FAC169051154867FB76974Le document en format XML
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Paul Stroemer</name><affiliation><mods:affiliation>ReNeuron Ltd., Guildford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Gorenkova, Natalia" sort="Gorenkova, Natalia" uniqKey="Gorenkova N" first="Natalia" last="Gorenkova">Natalia Gorenkova</name><affiliation><mods:affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Nakajima, Mitsuko" sort="Nakajima, Mitsuko" uniqKey="Nakajima M" first="Mitsuko" last="Nakajima">Mitsuko Nakajima</name><affiliation><mods:affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Crum, William R" sort="Crum, William R" uniqKey="Crum W" first="William R." last="Crum">William R. 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Sinden</name><affiliation><mods:affiliation>ReNeuron Ltd., Guildford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Modo, Michel" sort="Modo, Michel" uniqKey="Modo M" first="Michel" last="Modo">Michel Modo</name><affiliation><mods:affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Radiology, McGowan Centre for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Pittsburgh, McGowan Institute for Regenerative Medicine, 3025 East Carson Street, Pittsburgh, Pennsylvania 15203, USA</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:01782887DB1C4CEFD9FAC169051154867FB76974</idno><date when="2012" year="2012">2012</date><idno type="doi">10.1002/stem.1024</idno><idno type="url">https://api.istex.fr/document/01782887DB1C4CEFD9FAC169051154867FB76974/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001976</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001976</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Implantation Site and Lesion Topology Determine Efficacy of a Human Neural Stem Cell Line in a Rat Model of Chronic Stroke</title><author><name sortKey="Smith, Edward J" sort="Smith, Edward J" uniqKey="Smith E" first="Edward J." last="Smith">Edward J. Smith</name><affiliation><mods:affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</mods:affiliation></affiliation><affiliation><mods:affiliation>ReNeuron Ltd., Guildford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Stroemer, R Paul" sort="Stroemer, R Paul" uniqKey="Stroemer R" first="R. Paul" last="Stroemer">R. Paul Stroemer</name><affiliation><mods:affiliation>ReNeuron Ltd., Guildford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Gorenkova, Natalia" sort="Gorenkova, Natalia" uniqKey="Gorenkova N" first="Natalia" last="Gorenkova">Natalia Gorenkova</name><affiliation><mods:affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Nakajima, Mitsuko" sort="Nakajima, Mitsuko" uniqKey="Nakajima M" first="Mitsuko" last="Nakajima">Mitsuko Nakajima</name><affiliation><mods:affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Crum, William R" sort="Crum, William R" uniqKey="Crum W" first="William R." last="Crum">William R. Crum</name><affiliation><mods:affiliation>Department of Neuroimaging, King's College London, Institute of Psychiatry, London, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Tang, Ellen" sort="Tang, Ellen" uniqKey="Tang E" first="Ellen" last="Tang">Ellen Tang</name><affiliation><mods:affiliation>ReNeuron Ltd., Guildford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Stevanato, Lara" sort="Stevanato, Lara" uniqKey="Stevanato L" first="Lara" last="Stevanato">Lara Stevanato</name><affiliation><mods:affiliation>ReNeuron Ltd., Guildford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Sinden, John D" sort="Sinden, John D" uniqKey="Sinden J" first="John D." last="Sinden">John D. Sinden</name><affiliation><mods:affiliation>ReNeuron Ltd., Guildford, United Kingdom</mods:affiliation></affiliation></author><author><name sortKey="Modo, Michel" sort="Modo, Michel" uniqKey="Modo M" first="Michel" last="Modo">Michel Modo</name><affiliation><mods:affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</mods:affiliation></affiliation><affiliation><mods:affiliation>Department of Radiology, McGowan Centre for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>University of Pittsburgh, McGowan Institute for Regenerative Medicine, 3025 East Carson Street, Pittsburgh, Pennsylvania 15203, USA</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">STEM CELLS</title><title level="j" type="abbrev">STEM CELLS</title><idno type="ISSN">1066-5099</idno><idno type="eISSN">1549-4918</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2012-04">2012-04</date><biblScope unit="volume">30</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="785">785</biblScope><biblScope unit="page" to="796">796</biblScope></imprint><idno type="ISSN">1066-5099</idno></series><idno type="istex">01782887DB1C4CEFD9FAC169051154867FB76974</idno><idno type="DOI">10.1002/stem.1024</idno><idno type="ArticleID">STEM1024</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1066-5099</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Nervous system</term><term>Neural stem cell</term><term>Stem cell transplantation</term><term>Stroke</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Stroke remains one of the most promising targets for cell therapy. Thorough preclinical efficacy testing of human neural stem cell (hNSC) lines in a rat model of stroke (transient middle cerebral artery occlusion) is, however, required for translation into a clinical setting. Magnetic resonance imaging (MRI) here confirmed stroke damage and allowed the targeted injection of 450,000 hNSCs (CTX0E03) into peri‐infarct tissue, rather than the lesion cyst. Intraparenchymal cell implants improved sensorimotor dysfunctions (bilateral asymmetry test) and motor deficits (footfault test and rotameter). Importantly, analyses based on lesion topology (striatal vs. striatal + cortical damage) revealed a more significant improvement in animals with a stroke confined to the striatum. However, no improvement in learning and memory (water maze) was evident. An intracerebroventricular injection of cells did not result in any improvement. MRI‐based lesion, striatal and cortical volumes were unchanged in treated animals compared to those with stroke that received an intraparenchymal injection of suspension vehicle. Grafted cells only survived after intraparenchymal injection with a striatal + cortical topology resulting in better graft survival (16,026 cells) than in animals with smaller striatal lesions (2,374 cells). Almost 20% of cells differentiated into glial fibrillary acidic protein+ astrocytes, but <2% turned into FOX3+ neurons. These results indicate that CTX0E03 implants robustly recover behavioral dysfunction over a 3‐month time frame and that this effect is specific to their site of implantation. Lesion topology is potentially an important factor in the recovery, with a stroke confined to the striatum showing a better outcome compared to a larger area of damage. STEM CELLS 2012; 30:785–796</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Edward J. Smith</name><affiliations><json:string>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</json:string><json:string>ReNeuron Ltd., Guildford, United Kingdom</json:string></affiliations></json:item><json:item><name>R. Paul Stroemer</name><affiliations><json:string>ReNeuron Ltd., Guildford, United Kingdom</json:string></affiliations></json:item><json:item><name>Natalia Gorenkova</name><affiliations><json:string>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</json:string></affiliations></json:item><json:item><name>Mitsuko Nakajima</name><affiliations><json:string>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</json:string></affiliations></json:item><json:item><name>William R. Crum</name><affiliations><json:string>Department of Neuroimaging, King's College London, Institute of Psychiatry, London, United Kingdom</json:string></affiliations></json:item><json:item><name>Ellen Tang</name><affiliations><json:string>ReNeuron Ltd., Guildford, United Kingdom</json:string></affiliations></json:item><json:item><name>Lara Stevanato</name><affiliations><json:string>ReNeuron Ltd., Guildford, United Kingdom</json:string></affiliations></json:item><json:item><name>John D. Sinden</name><affiliations><json:string>ReNeuron Ltd., Guildford, United Kingdom</json:string></affiliations></json:item><json:item><name>Michel Modo</name><affiliations><json:string>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</json:string><json:string>Department of Radiology, McGowan Centre for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA</json:string><json:string>University of Pittsburgh, McGowan Institute for Regenerative Medicine, 3025 East Carson Street, Pittsburgh, Pennsylvania 15203, USA</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Stem cell transplantation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Neural stem cell</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Stroke</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Nervous system</value></json:item></subject><articleId><json:string>STEM1024</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>Stroke remains one of the most promising targets for cell therapy. Thorough preclinical efficacy testing of human neural stem cell (hNSC) lines in a rat model of stroke (transient middle cerebral artery occlusion) is, however, required for translation into a clinical setting. Magnetic resonance imaging (MRI) here confirmed stroke damage and allowed the targeted injection of 450,000 hNSCs (CTX0E03) into peri‐infarct tissue, rather than the lesion cyst. Intraparenchymal cell implants improved sensorimotor dysfunctions (bilateral asymmetry test) and motor deficits (footfault test and rotameter). Importantly, analyses based on lesion topology (striatal vs. striatal + cortical damage) revealed a more significant improvement in animals with a stroke confined to the striatum. However, no improvement in learning and memory (water maze) was evident. An intracerebroventricular injection of cells did not result in any improvement. MRI‐based lesion, striatal and cortical volumes were unchanged in treated animals compared to those with stroke that received an intraparenchymal injection of suspension vehicle. Grafted cells only survived after intraparenchymal injection with a striatal + cortical topology resulting in better graft survival (16,026 cells) than in animals with smaller striatal lesions (2,374 cells). Almost 20% of cells differentiated into glial fibrillary acidic protein+ astrocytes, but >2% turned into FOX3+ neurons. These results indicate that CTX0E03 implants robustly recover behavioral dysfunction over a 3‐month time frame and that this effect is specific to their site of implantation. Lesion topology is potentially an important factor in the recovery, with a stroke confined to the striatum showing a better outcome compared to a larger area of damage. 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medicine</json:string><json:string>immunology</json:string></scienceMetrix></categories><publicationDate>2012</publicationDate><copyrightDate>2012</copyrightDate><doi><json:string>10.1002/stem.1024</json:string></doi><id>01782887DB1C4CEFD9FAC169051154867FB76974</id><score>0.019739822</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/01782887DB1C4CEFD9FAC169051154867FB76974/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/01782887DB1C4CEFD9FAC169051154867FB76974/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/01782887DB1C4CEFD9FAC169051154867FB76974/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Implantation Site and Lesion Topology Determine Efficacy of a Human Neural Stem Cell Line in a Rat Model of Chronic Stroke</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><availability><p>Copyright © 2011 AlphaMed Press</p></availability><date>2012</date></publicationStmt><notesStmt><note type="content">*Authors contributions: E.J.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, and administrative support; R.P.S.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; N.G., M.N., W.R.C., E.T., and L.S.: collection and/or assembly of data, data analysis and interpretation, and manuscript writing; J.D.S.: conception and design, financial support, data analysis and interpretation, and manuscript writing; and M.M.: conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of manuscript.</note><note type="content">*Disclosure of potential conflicts of interest is found at the end of this article.</note><note type="content">*First published online in STEM CELLS EXPRESS December 29, 2011.</note><note>NIBIB Quantum - No. 1 P20 EB007076‐01;</note><note>MRC Translational Stem Cell Initiative - No. G0800846;</note><note>ReNeuron Ltd</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Implantation Site and Lesion Topology Determine Efficacy of a Human Neural Stem Cell Line in a Rat Model of Chronic Stroke</title><author xml:id="author-1"><persName><forename type="first">Edward J.</forename><surname>Smith</surname></persName><affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</affiliation><affiliation>ReNeuron Ltd., Guildford, United Kingdom</affiliation></author><author xml:id="author-2"><persName><forename type="first">R. Paul</forename><surname>Stroemer</surname></persName><affiliation>ReNeuron Ltd., Guildford, United Kingdom</affiliation></author><author xml:id="author-3"><persName><forename type="first">Natalia</forename><surname>Gorenkova</surname></persName><affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</affiliation></author><author xml:id="author-4"><persName><forename type="first">Mitsuko</forename><surname>Nakajima</surname></persName><affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</affiliation></author><author xml:id="author-5"><persName><forename type="first">William R.</forename><surname>Crum</surname></persName><affiliation>Department of Neuroimaging, King's College London, Institute of Psychiatry, London, United Kingdom</affiliation></author><author xml:id="author-6"><persName><forename type="first">Ellen</forename><surname>Tang</surname></persName><affiliation>ReNeuron Ltd., Guildford, United Kingdom</affiliation></author><author xml:id="author-7"><persName><forename type="first">Lara</forename><surname>Stevanato</surname></persName><affiliation>ReNeuron Ltd., Guildford, United Kingdom</affiliation></author><author xml:id="author-8"><persName><forename type="first">John D.</forename><surname>Sinden</surname></persName><affiliation>ReNeuron Ltd., Guildford, United Kingdom</affiliation></author><author xml:id="author-9"><persName><forename type="first">Michel</forename><surname>Modo</surname></persName><note type="biography">Telephone: 412‐383‐7200; Fax: (412) 647‐0878</note><affiliation>Telephone: 412‐383‐7200; Fax: (412) 647‐0878</affiliation><affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</affiliation><affiliation>Department of Radiology, McGowan Centre for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA</affiliation><affiliation>University of Pittsburgh, McGowan Institute for Regenerative Medicine, 3025 East Carson Street, Pittsburgh, Pennsylvania 15203, USA</affiliation></author></analytic><monogr><title level="j">STEM CELLS</title><title level="j" type="abbrev">STEM CELLS</title><idno type="pISSN">1066-5099</idno><idno type="eISSN">1549-4918</idno><idno type="DOI">10.1002/(ISSN)1549-4918</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2012-04"></date><biblScope unit="volume">30</biblScope><biblScope unit="issue">4</biblScope><biblScope unit="page" from="785">785</biblScope><biblScope unit="page" to="796">796</biblScope></imprint></monogr><idno type="istex">01782887DB1C4CEFD9FAC169051154867FB76974</idno><idno type="DOI">10.1002/stem.1024</idno><idno type="ArticleID">STEM1024</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2012</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Stroke remains one of the most promising targets for cell therapy. Thorough preclinical efficacy testing of human neural stem cell (hNSC) lines in a rat model of stroke (transient middle cerebral artery occlusion) is, however, required for translation into a clinical setting. Magnetic resonance imaging (MRI) here confirmed stroke damage and allowed the targeted injection of 450,000 hNSCs (CTX0E03) into peri‐infarct tissue, rather than the lesion cyst. Intraparenchymal cell implants improved sensorimotor dysfunctions (bilateral asymmetry test) and motor deficits (footfault test and rotameter). Importantly, analyses based on lesion topology (striatal vs. striatal + cortical damage) revealed a more significant improvement in animals with a stroke confined to the striatum. However, no improvement in learning and memory (water maze) was evident. An intracerebroventricular injection of cells did not result in any improvement. MRI‐based lesion, striatal and cortical volumes were unchanged in treated animals compared to those with stroke that received an intraparenchymal injection of suspension vehicle. Grafted cells only survived after intraparenchymal injection with a striatal + cortical topology resulting in better graft survival (16,026 cells) than in animals with smaller striatal lesions (2,374 cells). Almost 20% of cells differentiated into glial fibrillary acidic protein+ astrocytes, but <2% turned into FOX3+ neurons. These results indicate that CTX0E03 implants robustly recover behavioral dysfunction over a 3‐month time frame and that this effect is specific to their site of implantation. Lesion topology is potentially an important factor in the recovery, with a stroke confined to the striatum showing a better outcome compared to a larger area of damage. 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Paul</givenNames><familyName>Stroemer</familyName></personName></creator><creator xml:id="au3" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Natalia</givenNames><familyName>Gorenkova</familyName></personName></creator><creator xml:id="au4" creatorRole="author" affiliationRef="#af1"><personName><givenNames>Mitsuko</givenNames><familyName>Nakajima</familyName></personName></creator><creator xml:id="au5" creatorRole="author" affiliationRef="#af3"><personName><givenNames>William R.</givenNames><familyName>Crum</familyName></personName></creator><creator xml:id="au6" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Ellen</givenNames><familyName>Tang</familyName></personName></creator><creator xml:id="au7" creatorRole="author" affiliationRef="#af2"><personName><givenNames>Lara</givenNames><familyName>Stevanato</familyName></personName></creator><creator xml:id="au8" creatorRole="author" affiliationRef="#af2"><personName><givenNames>John D.</givenNames><familyName>Sinden</familyName></personName></creator><creator xml:id="au9" creatorRole="author" affiliationRef="#af1 #af4" corresponding="yes" noteRef="#fn2"><personName><givenNames>Michel</givenNames><familyName>Modo</familyName></personName><contactDetails><email>modomm@upmc.edu</email></contactDetails></creator></creators><affiliationGroup><affiliation xml:id="af1" countryCode="GB" type="organization"><unparsedAffiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</unparsedAffiliation></affiliation><affiliation xml:id="af2" countryCode="GB" type="organization"><unparsedAffiliation>ReNeuron Ltd., Guildford, United Kingdom</unparsedAffiliation></affiliation><affiliation xml:id="af3" countryCode="GB" type="organization"><unparsedAffiliation>Department of Neuroimaging, King's College London, Institute of Psychiatry, London, United Kingdom</unparsedAffiliation></affiliation><affiliation xml:id="af4" countryCode="US" type="organization"><unparsedAffiliation>Department of Radiology, McGowan Centre for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en" type="author"><keyword xml:id="kwd1">Stem cell transplantation</keyword><keyword xml:id="kwd2">Neural stem cell</keyword><keyword xml:id="kwd3">Stroke</keyword><keyword xml:id="kwd4">Nervous system</keyword></keywordGroup><fundingInfo><fundingAgency>NIBIB Quantum</fundingAgency><fundingNumber>1 P20 EB007076‐01</fundingNumber></fundingInfo><fundingInfo><fundingAgency>MRC Translational Stem Cell Initiative</fundingAgency><fundingNumber>G0800846</fundingNumber></fundingInfo><fundingInfo><fundingAgency>ReNeuron Ltd</fundingAgency></fundingInfo><supportingInformation><p> Additional Supporting Information may be found in the online version of this article. </p><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:10665099:media:stem1024:STEM_1024_sm_SuppFig1"></mediaResource><caption>Supplementary Figure 1. A priori power analysis of experiment. Power calculations (G*Power 3, University of Trier) based on previous data indicated that a group size of 12 animals per group will achieve a power (1‐β) of 95% at the 0.05 significance level (a) with an effect size (f) of 0.25 for repeated measures (4 repetitions) analyses of variances (ANOVA) considering within and between factors, as well as interactions. However, we need to include more animals than indicated by this calculation due to exclusion of animals' post‐hoc and potentially a smaller effect size (f=0.2). We previously determined that between 20‐30% of animals are excluded due to not having a lesion (i.e. a hyperintense T2 signal in striatum/cortex), haemorrhaging, or being outliers. Based on these assumptions, the power analysis indicated that a total sample size of 60 animals (n=15 per group) provides sufficient power to yield significant results in our primary outcome measure, the bilateral asymmetry test.</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:10665099:media:stem1024:STEM_1024_sm_SuppFig2"></mediaResource><caption>Supplementary Figure 2. Side‐effects of implantation surgery. B. Most animals showed minor damage that was caused by the injection, notably injection tract damage causing a light hypointense signal in the area of injection (top row images). This disappears fairly rapidly after injection and by 4 weeks post‐injection is no longer detectable. However, in a few animals, small blood clots (strong hypointense signal) and edema (hyperintense signal) around the injection tract could also be observed on T2‐weighted images. It is noteworthy that even this “major” injection damage subsides with time. B. Side‐effects, such as edema, tract damage, and small bleeds, can be seen in all groups equally. Less tract damage was evident in ICV implanted animals, as there was less tissue to penetrate.</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:10665099:media:stem1024:STEM_1024_sm_SuppFig3"></mediaResource><caption>Supplementary Figure 3. Endogenous neurogenesis – sub‐groups. Neither striatal, nor striatal+cortical, lesions significantly affected the length of the sub‐ependymal zone. The width in the rostral part of the subependymal zone was significantly enlarged and this was more evident in the large striatal+cortical lesions. However, the decrease in the caudal part of the sub‐ependymal zone compensated for this effect and resulted in no net increase in overall width of the subependymal zone.</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:10665099:media:stem1024:STEM_1024_sm_SuppTab1"></mediaResource><caption>Supplementary Table 1</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:10665099:media:stem1024:STEM_1024_sm_SuppTab2"></mediaResource><caption>Supplementary Table 2</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:10665099:media:stem1024:STEM_1024_sm_SuppTab3"></mediaResource><caption>Supplementary Table 3</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:10665099:media:stem1024:STEM_1024_sm_SuppTab4"></mediaResource><caption>Supplementary Table 4</caption></supportingInfoItem><supportingInfoItem><mediaResource alt="supporting information" href="urn-x:wiley:10665099:media:stem1024:STEM_1024_sm_SuppTab5"></mediaResource><caption>Supplementary Table 5</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:lang="en"><title type="main">Abstract</title><p>Stroke remains one of the most promising targets for cell therapy. Thorough preclinical efficacy testing of human neural stem cell (hNSC) lines in a rat model of stroke (transient middle cerebral artery occlusion) is, however, required for translation into a clinical setting. Magnetic resonance imaging (MRI) here confirmed stroke damage and allowed the targeted injection of 450,000 hNSCs (CTX0E03) into peri‐infarct tissue, rather than the lesion cyst. Intraparenchymal cell implants improved sensorimotor dysfunctions (bilateral asymmetry test) and motor deficits (footfault test and rotameter). Importantly, analyses based on lesion topology (striatal vs. striatal + cortical damage) revealed a more significant improvement in animals with a stroke confined to the striatum. However, no improvement in learning and memory (water maze) was evident. An intracerebroventricular injection of cells did not result in any improvement. MRI‐based lesion, striatal and cortical volumes were unchanged in treated animals compared to those with stroke that received an intraparenchymal injection of suspension vehicle. Grafted cells only survived after intraparenchymal injection with a striatal + cortical topology resulting in better graft survival (16,026 cells) than in animals with smaller striatal lesions (2,374 cells). Almost 20% of cells differentiated into glial fibrillary acidic protein+ astrocytes, but <2% turned into FOX3+ neurons. These results indicate that CTX0E03 implants robustly recover behavioral dysfunction over a 3‐month time frame and that this effect is specific to their site of implantation. Lesion topology is potentially an important factor in the recovery, with a stroke confined to the striatum showing a better outcome compared to a larger area of damage. S<sc>TEM</sc> C<sc>ELLS</sc> <i>2012; 30:785–796</i></p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="fn1"><p>Authors contributions: E.J.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, and administrative support; R.P.S.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; N.G., M.N., W.R.C., E.T., and L.S.: collection and/or assembly of data, data analysis and interpretation, and manuscript writing; J.D.S.: conception and design, financial support, data analysis and interpretation, and manuscript writing; and M.M.: conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of manuscript.</p></note><note xml:id="fn3"><p>Disclosure of potential conflicts of interest is found at the end of this article.</p></note><note xml:id="fn4"><p>First published online in S<sc>TEM</sc> C<sc>ELLS</sc> <i>EXPRESS</i> December 29, 2011.</p></note><note xml:id="fn2"><p>Telephone: 412‐383‐7200; Fax: (412) 647‐0878</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Implantation Site and Lesion Topology Determine Efficacy of a Human Neural Stem Cell Line in a Rat Model of Chronic Stroke</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>Efficacy of hNSCs in Chronic Stroke</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Implantation Site and Lesion Topology Determine Efficacy of a Human Neural Stem Cell Line in a Rat Model of Chronic Stroke</title></titleInfo><name type="personal"><namePart type="given">Edward J.</namePart><namePart type="family">Smith</namePart><affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</affiliation><affiliation>ReNeuron Ltd., Guildford, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">R. Paul</namePart><namePart type="family">Stroemer</namePart><affiliation>ReNeuron Ltd., Guildford, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Natalia</namePart><namePart type="family">Gorenkova</namePart><affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mitsuko</namePart><namePart type="family">Nakajima</namePart><affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">William R.</namePart><namePart type="family">Crum</namePart><affiliation>Department of Neuroimaging, King's College London, Institute of Psychiatry, London, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Ellen</namePart><namePart type="family">Tang</namePart><affiliation>ReNeuron Ltd., Guildford, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lara</namePart><namePart type="family">Stevanato</namePart><affiliation>ReNeuron Ltd., Guildford, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">John D.</namePart><namePart type="family">Sinden</namePart><affiliation>ReNeuron Ltd., Guildford, United Kingdom</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michel</namePart><namePart type="family">Modo</namePart><affiliation>Department of Neuroscience, King's College London, Institute of Psychiatry, London, United Kingdom</affiliation><affiliation>Department of Radiology, McGowan Centre for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA</affiliation><description>Telephone: 412‐383‐7200; Fax: (412) 647‐0878</description><affiliation>University of Pittsburgh, McGowan Institute for Regenerative Medicine, 3025 East Carson Street, Pittsburgh, Pennsylvania 15203, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><place><placeTerm type="text">Hoboken</placeTerm></place><dateIssued encoding="w3cdtf">2012-04</dateIssued><dateCaptured encoding="w3cdtf">2011-11-10</dateCaptured><dateValid encoding="w3cdtf">2011-12-12</dateValid><copyrightDate encoding="w3cdtf">2012</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="figures">6</extent><extent unit="references">35</extent><extent unit="words">8243</extent></physicalDescription><abstract lang="en">Stroke remains one of the most promising targets for cell therapy. Thorough preclinical efficacy testing of human neural stem cell (hNSC) lines in a rat model of stroke (transient middle cerebral artery occlusion) is, however, required for translation into a clinical setting. Magnetic resonance imaging (MRI) here confirmed stroke damage and allowed the targeted injection of 450,000 hNSCs (CTX0E03) into peri‐infarct tissue, rather than the lesion cyst. Intraparenchymal cell implants improved sensorimotor dysfunctions (bilateral asymmetry test) and motor deficits (footfault test and rotameter). Importantly, analyses based on lesion topology (striatal vs. striatal + cortical damage) revealed a more significant improvement in animals with a stroke confined to the striatum. However, no improvement in learning and memory (water maze) was evident. An intracerebroventricular injection of cells did not result in any improvement. MRI‐based lesion, striatal and cortical volumes were unchanged in treated animals compared to those with stroke that received an intraparenchymal injection of suspension vehicle. Grafted cells only survived after intraparenchymal injection with a striatal + cortical topology resulting in better graft survival (16,026 cells) than in animals with smaller striatal lesions (2,374 cells). Almost 20% of cells differentiated into glial fibrillary acidic protein+ astrocytes, but <2% turned into FOX3+ neurons. These results indicate that CTX0E03 implants robustly recover behavioral dysfunction over a 3‐month time frame and that this effect is specific to their site of implantation. Lesion topology is potentially an important factor in the recovery, with a stroke confined to the striatum showing a better outcome compared to a larger area of damage. STEM CELLS 2012; 30:785–796</abstract><note type="content">*Authors contributions: E.J.S.: collection and/or assembly of data, data analysis and interpretation, manuscript writing, and administrative support; R.P.S.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; N.G., M.N., W.R.C., E.T., and L.S.: collection and/or assembly of data, data analysis and interpretation, and manuscript writing; J.D.S.: conception and design, financial support, data analysis and interpretation, and manuscript writing; and M.M.: conception and design, financial support, data analysis and interpretation, manuscript writing, and final approval of manuscript.</note><note type="content">*Disclosure of potential conflicts of interest is found at the end of this article.</note><note type="content">*First published online in STEM CELLS EXPRESS December 29, 2011.</note><note type="funding">NIBIB Quantum - No. 1 P20 EB007076‐01; </note><note type="funding">MRC Translational Stem Cell Initiative - No. G0800846; </note><note type="funding">ReNeuron Ltd</note><subject lang="en"><genre>keywords</genre><topic>Stem cell transplantation</topic><topic>Neural stem cell</topic><topic>Stroke</topic><topic>Nervous system</topic></subject><relatedItem type="host"><titleInfo><title>STEM CELLS</title></titleInfo><titleInfo type="abbreviated"><title>STEM CELLS</title></titleInfo><genre type="journal">journal</genre><note type="content"> Additional Supporting Information may be found in the online version of this article.Supporting Info Item: Supplementary Figure 1. A priori power analysis of experiment. Power calculations (G*Power 3, University of Trier) based on previous data indicated that a group size of 12 animals per group will achieve a power (1‐β) of 95% at the 0.05 significance level (a) with an effect size (f) of 0.25 for repeated measures (4 repetitions) analyses of variances (ANOVA) considering within and between factors, as well as interactions. However, we need to include more animals than indicated by this calculation due to exclusion of animals' post‐hoc and potentially a smaller effect size (f=0.2). We previously determined that between 20‐30% of animals are excluded due to not having a lesion (i.e. a hyperintense T2 signal in striatum/cortex), haemorrhaging, or being outliers. Based on these assumptions, the power analysis indicated that a total sample size of 60 animals (n=15 per group) provides sufficient power to yield significant results in our primary outcome measure, the bilateral asymmetry test. - Supplementary Figure 2. Side‐effects of implantation surgery. B. Most animals showed minor damage that was caused by the injection, notably injection tract damage causing a light hypointense signal in the area of injection (top row images). This disappears fairly rapidly after injection and by 4 weeks post‐injection is no longer detectable. However, in a few animals, small blood clots (strong hypointense signal) and edema (hyperintense signal) around the injection tract could also be observed on T2‐weighted images. It is noteworthy that even this “major” injection damage subsides with time. B. Side‐effects, such as edema, tract damage, and small bleeds, can be seen in all groups equally. Less tract damage was evident in ICV implanted animals, as there was less tissue to penetrate. - Supplementary Figure 3. Endogenous neurogenesis – sub‐groups. Neither striatal, nor striatal+cortical, lesions significantly affected the length of the sub‐ependymal zone. The width in the rostral part of the subependymal zone was significantly enlarged and this was more evident in the large striatal+cortical lesions. However, the decrease in the caudal part of the sub‐ependymal zone compensated for this effect and resulted in no net increase in overall width of the subependymal zone. - Supplementary Table 1 - Supplementary Table 2 - Supplementary Table 3 - Supplementary Table 4 - Supplementary Table 5 - </note><subject><genre>article-category</genre><topic>Translational and Clinical Research</topic></subject><identifier type="ISSN">1066-5099</identifier><identifier type="eISSN">1549-4918</identifier><identifier type="DOI">10.1002/(ISSN)1549-4918</identifier><identifier type="PublisherID">STEM</identifier><part><date>2012</date><detail type="volume"><caption>vol.</caption><number>30</number></detail><detail type="issue"><caption>no.</caption><number>4</number></detail><extent unit="pages"><start>785</start><end>796</end><total>12</total></extent></part></relatedItem><identifier type="istex">01782887DB1C4CEFD9FAC169051154867FB76974</identifier><identifier type="DOI">10.1002/stem.1024</identifier><identifier type="ArticleID">STEM1024</identifier><accessCondition type="use and reproduction" contentType="copyright">Copyright © 2011 AlphaMed Press</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Wiley Subscription Services, Inc., A Wiley Company</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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