Endogenous cerebellar neurogenesis in adult mice with progressive ataxia
Identifieur interne : 000375 ( Pmc/Checkpoint ); précédent : 000374; suivant : 000376Endogenous cerebellar neurogenesis in adult mice with progressive ataxia
Auteurs : Manoj Kumar [France] ; Zsolt Csaba [France] ; Stéphane Peineau [France, Royaume-Uni] ; Rupali Srivastava [France, Inde] ; Sowmyalakshmi Rasika [France] ; Shyamala Mani [Inde] ; Pierre Gressens [France, Royaume-Uni] ; Vincent El Ghouzzi [France]Source :
- Annals of Clinical and Translational Neurology [ 2328-9503 ] ; 2014.
Abstract
Transplanting exogenous neuronal progenitors to replace damaged neurons in the adult brain following injury or neurodegenerative disorders and achieve functional amelioration is a realistic goal. However, studies so far have rarely taken into consideration the preexisting inflammation triggered by the disease process that could hamper the effectiveness of transplanted cells. Here, we examined the fate and long-term consequences of human cerebellar granule neuron precursors (GNP) transplanted into the cerebellum of Harlequin mice, an adult model of progressive cerebellar degeneration with early-onset microgliosis.
Human embryonic stem cell-derived progenitors expressing Atoh1, a transcription factor key to GNP specification, were generated in vitro and stereotaxically transplanted into the cerebellum of preataxic Harlequin mice. The histological and functional impact of these transplants was followed using immunolabeling and Rotarod analysis.
Although transplanted GNPs did not survive beyond a few weeks, they triggered the proliferation of endogenous nestin-positive precursors in the leptomeninges that crossed the molecular layer and differentiated into mature neurons. These phenomena were accompanied by the preservation of the granule and Purkinje cell layers and delayed ataxic changes. In vitro neurosphere generation confirmed the enhanced neurogenic potential of the cerebellar leptomeninges of Harlequin mice transplanted with exogenous GNPs.
The cerebellar leptomeninges of adult mice contain an endogenous neurogenic niche that can be stimulated to yield mature neurons from an as-yet unidentified population of progenitors. The transplantation of human GNPs not only stimulates this neurogenesis, but, despite the potentially hostile environment, leads to neuroprotection and functional amelioration.
Url:
DOI: 10.1002/acn3.137
PubMed: 25574472
PubMed Central: 4284123
Affiliations:
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<front><div type="abstract" xml:lang="en"><sec><title>Objective</title>
<p>Transplanting exogenous neuronal progenitors to replace damaged neurons in the adult brain following injury or neurodegenerative disorders and achieve functional amelioration is a realistic goal. However, studies so far have rarely taken into consideration the preexisting inflammation triggered by the disease process that could hamper the effectiveness of transplanted cells. Here, we examined the fate and long-term consequences of human cerebellar granule neuron precursors (GNP) transplanted into the cerebellum of Harlequin mice, an adult model of progressive cerebellar degeneration with early-onset microgliosis.</p>
</sec>
<sec><title>Methods</title>
<p>Human embryonic stem cell-derived progenitors expressing Atoh1, a transcription factor key to GNP specification, were generated in vitro and stereotaxically transplanted into the cerebellum of preataxic Harlequin mice. The histological and functional impact of these transplants was followed using immunolabeling and Rotarod analysis.</p>
</sec>
<sec><title>Results</title>
<p>Although transplanted GNPs did not survive beyond a few weeks, they triggered the proliferation of endogenous nestin-positive precursors in the leptomeninges that crossed the molecular layer and differentiated into mature neurons. These phenomena were accompanied by the preservation of the granule and Purkinje cell layers and delayed ataxic changes. In vitro neurosphere generation confirmed the enhanced neurogenic potential of the cerebellar leptomeninges of Harlequin mice transplanted with exogenous GNPs.</p>
</sec>
<sec><title>Interpretation</title>
<p>The cerebellar leptomeninges of adult mice contain an endogenous neurogenic niche that can be stimulated to yield mature neurons from an as-yet unidentified population of progenitors. The transplantation of human GNPs not only stimulates this neurogenesis, but, despite the potentially hostile environment, leads to neuroprotection and functional amelioration.</p>
</sec>
</div>
</front>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Ann Clin Transl Neurol</journal-id>
<journal-id journal-id-type="iso-abbrev">Ann Clin Transl Neurol</journal-id>
<journal-id journal-id-type="publisher-id">acn3</journal-id>
<journal-title-group><journal-title>Annals of Clinical and Translational Neurology</journal-title>
</journal-title-group>
<issn pub-type="ppub">2328-9503</issn>
<issn pub-type="epub">2328-9503</issn>
<publisher><publisher-name>Blackwell Publishing Ltd</publisher-name>
<publisher-loc>Oxford, UK</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">25574472</article-id>
<article-id pub-id-type="pmc">4284123</article-id>
<article-id pub-id-type="doi">10.1002/acn3.137</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Articles</subject>
</subj-group>
</article-categories>
<title-group><article-title>Endogenous cerebellar neurogenesis in adult mice with progressive ataxia</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kumar</surname>
<given-names>Manoj</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="aff" rid="au2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Csaba</surname>
<given-names>Zsolt</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="aff" rid="au2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Peineau</surname>
<given-names>Stéphane</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="aff" rid="au2">2</xref>
<xref ref-type="aff" rid="au3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Srivastava</surname>
<given-names>Rupali</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="aff" rid="au2">2</xref>
<xref ref-type="aff" rid="au4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rasika</surname>
<given-names>Sowmyalakshmi</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="aff" rid="au2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mani</surname>
<given-names>Shyamala</given-names>
</name>
<xref ref-type="aff" rid="au5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gressens</surname>
<given-names>Pierre</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="aff" rid="au2">2</xref>
<xref ref-type="aff" rid="au6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>El Ghouzzi</surname>
<given-names>Vincent</given-names>
</name>
<xref ref-type="aff" rid="au1">1</xref>
<xref ref-type="aff" rid="au2">2</xref>
</contrib>
<aff id="au1"><label>1</label>
<institution>Inserm U1141</institution>
<addr-line>Paris, France</addr-line>
</aff>
<aff id="au2"><label>2</label>
<institution>Sorbonne Paris Cité, Université Paris Diderot, UMRS 1141</institution>
<addr-line>Paris, France</addr-line>
</aff>
<aff id="au3"><label>3</label>
<institution>School of Physiology and Pharmacology, MRC Centre for Synaptic Plasticity</institution>
<addr-line>Bristol, United Kingdom</addr-line>
</aff>
<aff id="au4"><label>4</label>
<institution>National Brain Research Centre</institution>
<addr-line>Manesar, India</addr-line>
</aff>
<aff id="au5"><label>5</label>
<institution>Centre for Neuroscience, IISC</institution>
<addr-line>Bangalore, India</addr-line>
</aff>
<aff id="au6"><label>6</label>
<institution>Department of Division of Imaging Sciences and Biomedical Engineering, Centre for the Developing Brain, King's College London, King's Health Partners, St. Thomas' Hospital</institution>
<addr-line>London, United Kingdom</addr-line>
</aff>
</contrib-group>
<author-notes><corresp id="cor1">Vincent El Ghouzzi, Inserm U1141, Hôpital Robert-Debré, 48 Boulevard Sérurier, F-75019 Paris, France. Tel: +331 40031973; Fax: +331 40031995; E-mail: <email>vincent.elghouzzi@inserm.fr</email>
</corresp>
<fn><p><bold>Funding Information</bold>
This study was supported by the Institut National pour la Santé et la Recherche Médicale (Inserm), the Centre National de la Recherche Scientifique (CNRS), the Université Paris7, the DHU PROTECT and grants from IFCPAR/CEFIPRA (project nos. 3803-3 and 4903-2), the French National Research Agency (project ANR-09-GENO-007), the Princesse Gràce de Monaco Foundation and the Roger de Spoelberch Foundation. M. K. was supported by the Inserm and ANR contract no. ANR-09-GENO-007 to V. E. G.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><month>12</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub"><day>04</day>
<month>11</month>
<year>2014</year>
</pub-date>
<volume>1</volume>
<issue>12</issue>
<fpage>968</fpage>
<lpage>981</lpage>
<history><date date-type="received"><day>08</day>
<month>10</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>10</day>
<month>10</month>
<year>2014</year>
</date>
</history>
<permissions><copyright-statement>© 2014 The Authors. <italic>Annals of Clinical and Translational Neurology</italic>
published by Wiley Periodicals, Inc on behalf of American Neurological Association.</copyright-statement>
<copyright-year>2014</copyright-year>
<license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><license-p>This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.</license-p>
</license>
</permissions>
<abstract><sec><title>Objective</title>
<p>Transplanting exogenous neuronal progenitors to replace damaged neurons in the adult brain following injury or neurodegenerative disorders and achieve functional amelioration is a realistic goal. However, studies so far have rarely taken into consideration the preexisting inflammation triggered by the disease process that could hamper the effectiveness of transplanted cells. Here, we examined the fate and long-term consequences of human cerebellar granule neuron precursors (GNP) transplanted into the cerebellum of Harlequin mice, an adult model of progressive cerebellar degeneration with early-onset microgliosis.</p>
</sec>
<sec><title>Methods</title>
<p>Human embryonic stem cell-derived progenitors expressing Atoh1, a transcription factor key to GNP specification, were generated in vitro and stereotaxically transplanted into the cerebellum of preataxic Harlequin mice. The histological and functional impact of these transplants was followed using immunolabeling and Rotarod analysis.</p>
</sec>
<sec><title>Results</title>
<p>Although transplanted GNPs did not survive beyond a few weeks, they triggered the proliferation of endogenous nestin-positive precursors in the leptomeninges that crossed the molecular layer and differentiated into mature neurons. These phenomena were accompanied by the preservation of the granule and Purkinje cell layers and delayed ataxic changes. In vitro neurosphere generation confirmed the enhanced neurogenic potential of the cerebellar leptomeninges of Harlequin mice transplanted with exogenous GNPs.</p>
</sec>
<sec><title>Interpretation</title>
<p>The cerebellar leptomeninges of adult mice contain an endogenous neurogenic niche that can be stimulated to yield mature neurons from an as-yet unidentified population of progenitors. The transplantation of human GNPs not only stimulates this neurogenesis, but, despite the potentially hostile environment, leads to neuroprotection and functional amelioration.</p>
</sec>
</abstract>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>France</li>
<li>Inde</li>
<li>Royaume-Uni</li>
</country>
</list>
<tree><country name="France"><noRegion><name sortKey="Kumar, Manoj" sort="Kumar, Manoj" uniqKey="Kumar M" first="Manoj" last="Kumar">Manoj Kumar</name>
</noRegion>
<name sortKey="Csaba, Zsolt" sort="Csaba, Zsolt" uniqKey="Csaba Z" first="Zsolt" last="Csaba">Zsolt Csaba</name>
<name sortKey="Csaba, Zsolt" sort="Csaba, Zsolt" uniqKey="Csaba Z" first="Zsolt" last="Csaba">Zsolt Csaba</name>
<name sortKey="El Ghouzzi, Vincent" sort="El Ghouzzi, Vincent" uniqKey="El Ghouzzi V" first="Vincent" last="El Ghouzzi">Vincent El Ghouzzi</name>
<name sortKey="El Ghouzzi, Vincent" sort="El Ghouzzi, Vincent" uniqKey="El Ghouzzi V" first="Vincent" last="El Ghouzzi">Vincent El Ghouzzi</name>
<name sortKey="Gressens, Pierre" sort="Gressens, Pierre" uniqKey="Gressens P" first="Pierre" last="Gressens">Pierre Gressens</name>
<name sortKey="Gressens, Pierre" sort="Gressens, Pierre" uniqKey="Gressens P" first="Pierre" last="Gressens">Pierre Gressens</name>
<name sortKey="Kumar, Manoj" sort="Kumar, Manoj" uniqKey="Kumar M" first="Manoj" last="Kumar">Manoj Kumar</name>
<name sortKey="Peineau, Stephane" sort="Peineau, Stephane" uniqKey="Peineau S" first="Stéphane" last="Peineau">Stéphane Peineau</name>
<name sortKey="Peineau, Stephane" sort="Peineau, Stephane" uniqKey="Peineau S" first="Stéphane" last="Peineau">Stéphane Peineau</name>
<name sortKey="Rasika, Sowmyalakshmi" sort="Rasika, Sowmyalakshmi" uniqKey="Rasika S" first="Sowmyalakshmi" last="Rasika">Sowmyalakshmi Rasika</name>
<name sortKey="Rasika, Sowmyalakshmi" sort="Rasika, Sowmyalakshmi" uniqKey="Rasika S" first="Sowmyalakshmi" last="Rasika">Sowmyalakshmi Rasika</name>
<name sortKey="Srivastava, Rupali" sort="Srivastava, Rupali" uniqKey="Srivastava R" first="Rupali" last="Srivastava">Rupali Srivastava</name>
<name sortKey="Srivastava, Rupali" sort="Srivastava, Rupali" uniqKey="Srivastava R" first="Rupali" last="Srivastava">Rupali Srivastava</name>
</country>
<country name="Royaume-Uni"><noRegion><name sortKey="Peineau, Stephane" sort="Peineau, Stephane" uniqKey="Peineau S" first="Stéphane" last="Peineau">Stéphane Peineau</name>
</noRegion>
<name sortKey="Gressens, Pierre" sort="Gressens, Pierre" uniqKey="Gressens P" first="Pierre" last="Gressens">Pierre Gressens</name>
</country>
<country name="Inde"><noRegion><name sortKey="Srivastava, Rupali" sort="Srivastava, Rupali" uniqKey="Srivastava R" first="Rupali" last="Srivastava">Rupali Srivastava</name>
</noRegion>
<name sortKey="Mani, Shyamala" sort="Mani, Shyamala" uniqKey="Mani S" first="Shyamala" last="Mani">Shyamala Mani</name>
</country>
</tree>
</affiliations>
</record>
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