Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells
Identifieur interne : 002486 ( Main/Exploration ); précédent : 002485; suivant : 002487Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells
Auteurs : D. Eugene Redmond ; Kimberly B. Bjugstad [États-Unis] ; Yang D. Teng [États-Unis] ; Vaclav Ourednik [États-Unis] ; Jitka Ourednik [États-Unis] ; Dustin R. Wakeman [États-Unis] ; Xuejun H. Parsons [États-Unis] ; Rodolfo Gonzalez [États-Unis] ; Barbara C. Blanchard [États-Unis] ; Seung U. Kim [Canada] ; Zezong Gu [États-Unis] ; Stuart A. Lipton [États-Unis] ; Eleni A. Markakis ; Robert H. Roth [États-Unis] ; John D. Elsworth [États-Unis] ; John R. Sladek [États-Unis] ; Richard L. Sidman [États-Unis] ; Evan Y. Snyder [États-Unis]Source :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2007.
Abstract
Stem cells have been widely assumed to be capable of replacing lost or damaged cells in a number of diseases, including Parkinson's disease (PD), in which neurons of the substantia nigra (SN) die and fail to provide the neurotransmitter, dopamine (DA), to the striatum. We report that undifferentiated human neural stem cells (hNSCs) implanted into 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated Parkinsonian primates survived, migrated, and had a functional impact as assessed quantitatively by behavioral improvement in this DA-deficit model, in which Parkinsonian signs directly correlate to reduced DA levels. A small number of hNSC progeny differentiated into tyrosine hydroxylase (TH) and/or dopamine transporter (DAT) immunopositive cells, suggesting that the microenvironment within and around the lesioned adult host SN still permits development of a DA phenotype by responsive progenitor cells. A much larger number of hNSC-derived cells that did not express neuronal or DA markers was found arrayed along the persisting nigrostriatal path, juxtaposed with host cells. These hNSCs, which express DA-protective factors, were therefore well positioned to influence host TH+ cells and mediate other homeostatic adjustments, as reflected in a return to baseline endogenous neuronal number-to-size ratios, preservation of extant host nigrostriatal circuitry, and a normalizing effect on α-synuclein aggregation. We propose that multiple modes of reciprocal interaction between exogenous hNSCs and the pathological host milieu underlie the functional improvement observed in this model of PD.
Url:
DOI: 10.1073/pnas.0704091104
PubMed: 17586681
PubMed Central: 1896134
Affiliations:
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Eugene" last="Redmond">D. Eugene Redmond</name><affiliation><nlm:aff id="aff1">Departments of *Psychiatry,</nlm:aff></affiliation><affiliation><nlm:aff wicri:cut=", and" id="aff2">Neurosurgery</nlm:aff></affiliation></author><author><name sortKey="Bjugstad, Kimberly B" sort="Bjugstad, Kimberly B" uniqKey="Bjugstad K" first="Kimberly B." last="Bjugstad">Kimberly B. Bjugstad</name><affiliation wicri:level="2"><nlm:aff id="aff4">Department of Psychiatry, University of Colorado, Aurora, CO 80045;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>Department of Psychiatry, University of Colorado, Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Teng, Yang D" sort="Teng, Yang D" uniqKey="Teng Y" first="Yang D." last="Teng">Yang D. Teng</name><affiliation wicri:level="2"><nlm:aff id="aff5">Departments of Neurology and Neurosurgery, Harvard Medical School, Children's Hospital and Beth Israel Deaconess Medical Center, Division of Spinal Cord Injury Research, Veterans Affairs Boston Healthcare System, Boston, MA 02115;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Departments of Neurology and Neurosurgery, Harvard Medical School, Children's Hospital and Beth Israel Deaconess Medical Center, Division of Spinal Cord Injury Research, Veterans Affairs Boston Healthcare System, Boston</wicri:cityArea></affiliation></author><author><name sortKey="Ourednik, Vaclav" sort="Ourednik, Vaclav" uniqKey="Ourednik V" first="Vaclav" last="Ourednik">Vaclav Ourednik</name><affiliation wicri:level="2"><nlm:aff id="aff5">Departments of Neurology and Neurosurgery, Harvard Medical School, Children's Hospital and Beth Israel Deaconess Medical Center, Division of Spinal Cord Injury Research, Veterans Affairs Boston Healthcare System, Boston, MA 02115;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Departments of Neurology and Neurosurgery, Harvard Medical School, Children's Hospital and Beth Israel Deaconess Medical Center, Division of Spinal Cord Injury Research, Veterans Affairs Boston Healthcare System, Boston</wicri:cityArea></affiliation></author><author><name sortKey="Ourednik, Jitka" sort="Ourednik, Jitka" uniqKey="Ourednik J" first="Jitka" last="Ourednik">Jitka Ourednik</name><affiliation wicri:level="2"><nlm:aff id="aff5">Departments of Neurology and Neurosurgery, Harvard Medical School, Children's Hospital and Beth Israel Deaconess Medical Center, Division of Spinal Cord Injury Research, Veterans Affairs Boston Healthcare System, Boston, MA 02115;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Departments of Neurology and Neurosurgery, Harvard Medical School, Children's Hospital and Beth Israel Deaconess Medical Center, Division of Spinal Cord Injury Research, Veterans Affairs Boston Healthcare System, Boston</wicri:cityArea></affiliation></author><author><name sortKey="Wakeman, Dustin R" sort="Wakeman, Dustin R" uniqKey="Wakeman D" first="Dustin R." last="Wakeman">Dustin R. Wakeman</name><affiliation wicri:level="2"><nlm:aff id="aff6">**Burnham Institute for Medical Research, La Jolla, CA 92037;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>**Burnham Institute for Medical Research, La Jolla</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="aff8">Biomedical Sciences and Molecular Pathology Programs, University of California at San Diego, La Jolla, CA 92093</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Biomedical Sciences and Molecular Pathology Programs, University of California at San Diego, La Jolla</wicri:cityArea></affiliation></author><author><name sortKey="Parsons, Xuejun H" sort="Parsons, Xuejun H" uniqKey="Parsons X" first="Xuejun H." last="Parsons">Xuejun H. Parsons</name><affiliation wicri:level="2"><nlm:aff id="aff6">**Burnham Institute for Medical Research, La Jolla, CA 92037;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>**Burnham Institute for Medical Research, La Jolla</wicri:cityArea></affiliation></author><author><name sortKey="Gonzalez, Rodolfo" sort="Gonzalez, Rodolfo" uniqKey="Gonzalez R" first="Rodolfo" last="Gonzalez">Rodolfo Gonzalez</name><affiliation wicri:level="2"><nlm:aff id="aff6">**Burnham Institute for Medical Research, La Jolla, CA 92037;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>**Burnham Institute for Medical Research, La Jolla</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="aff8">Biomedical Sciences and Molecular Pathology Programs, University of California at San Diego, La Jolla, CA 92093</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Biomedical Sciences and Molecular Pathology Programs, University of California at San Diego, La Jolla</wicri:cityArea></affiliation></author><author><name sortKey="Blanchard, Barbara C" sort="Blanchard, Barbara C" uniqKey="Blanchard B" first="Barbara C." last="Blanchard">Barbara C. Blanchard</name><affiliation wicri:level="2"><nlm:aff id="aff4">Department of Psychiatry, University of Colorado, Aurora, CO 80045;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>Department of Psychiatry, University of Colorado, Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Kim, Seung U" sort="Kim, Seung U" uniqKey="Kim S" first="Seung U." last="Kim">Seung U. Kim</name><affiliation wicri:level="1"><nlm:aff wicri:cut="; and" id="aff7">Department of Neurology, University of British Columbia, Vancouver, BC, Canada V6T 2B5</nlm:aff><country>Canada</country><wicri:regionArea>Department of Neurology, University of British Columbia, Vancouver, BC</wicri:regionArea><wicri:noRegion>BC</wicri:noRegion></affiliation></author><author><name sortKey="Gu, Zezong" sort="Gu, Zezong" uniqKey="Gu Z" first="Zezong" last="Gu">Zezong Gu</name><affiliation wicri:level="2"><nlm:aff id="aff6">**Burnham Institute for Medical Research, La Jolla, CA 92037;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>**Burnham Institute for Medical Research, La Jolla</wicri:cityArea></affiliation></author><author><name sortKey="Lipton, Stuart A" sort="Lipton, Stuart A" uniqKey="Lipton S" first="Stuart A." last="Lipton">Stuart A. Lipton</name><affiliation wicri:level="2"><nlm:aff id="aff6">**Burnham Institute for Medical Research, La Jolla, CA 92037;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>**Burnham Institute for Medical Research, La Jolla</wicri:cityArea></affiliation></author><author><name sortKey="Markakis, Eleni A" sort="Markakis, Eleni A" uniqKey="Markakis E" first="Eleni A." last="Markakis">Eleni A. Markakis</name><affiliation><nlm:aff id="aff1">Departments of *Psychiatry,</nlm:aff></affiliation></author><author><name sortKey="Roth, Robert H" sort="Roth, Robert H" uniqKey="Roth R" first="Robert H." last="Roth">Robert H. Roth</name><affiliation><nlm:aff id="aff1">Departments of *Psychiatry,</nlm:aff></affiliation><affiliation wicri:level="2"><nlm:aff id="aff3">Pharmacology, Yale University School of Medicine, New Haven, CT 06510;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Connecticut</region></placeName><wicri:cityArea>Pharmacology, Yale University School of Medicine, New Haven</wicri:cityArea></affiliation></author><author><name sortKey="Elsworth, John D" sort="Elsworth, John D" uniqKey="Elsworth J" first="John D." last="Elsworth">John D. Elsworth</name><affiliation><nlm:aff id="aff1">Departments of *Psychiatry,</nlm:aff></affiliation><affiliation wicri:level="2"><nlm:aff id="aff3">Pharmacology, Yale University School of Medicine, New Haven, CT 06510;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Connecticut</region></placeName><wicri:cityArea>Pharmacology, Yale University School of Medicine, New Haven</wicri:cityArea></affiliation></author><author><name sortKey="Sladek, John R" sort="Sladek, John R" uniqKey="Sladek J" first="John R." last="Sladek">John R. Sladek</name><affiliation wicri:level="2"><nlm:aff id="aff4">Department of Psychiatry, University of Colorado, Aurora, CO 80045;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Colorado</region></placeName><wicri:cityArea>Department of Psychiatry, University of Colorado, Aurora</wicri:cityArea></affiliation></author><author><name sortKey="Sidman, Richard L" sort="Sidman, Richard L" uniqKey="Sidman R" first="Richard L." last="Sidman">Richard L. Sidman</name><affiliation wicri:level="2"><nlm:aff id="aff5">Departments of Neurology and Neurosurgery, Harvard Medical School, Children's Hospital and Beth Israel Deaconess Medical Center, Division of Spinal Cord Injury Research, Veterans Affairs Boston Healthcare System, Boston, MA 02115;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Departments of Neurology and Neurosurgery, Harvard Medical School, Children's Hospital and Beth Israel Deaconess Medical Center, Division of Spinal Cord Injury Research, Veterans Affairs Boston Healthcare System, Boston</wicri:cityArea></affiliation></author><author><name sortKey="Snyder, Evan Y" sort="Snyder, Evan Y" uniqKey="Snyder E" first="Evan Y." last="Snyder">Evan Y. Snyder</name><affiliation wicri:level="2"><nlm:aff id="aff5">Departments of Neurology and Neurosurgery, Harvard Medical School, Children's Hospital and Beth Israel Deaconess Medical Center, Division of Spinal Cord Injury Research, Veterans Affairs Boston Healthcare System, Boston, MA 02115;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea>Departments of Neurology and Neurosurgery, Harvard Medical School, Children's Hospital and Beth Israel Deaconess Medical Center, Division of Spinal Cord Injury Research, Veterans Affairs Boston Healthcare System, Boston</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="aff6">**Burnham Institute for Medical Research, La Jolla, CA 92037;</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>**Burnham Institute for Medical Research, La Jolla</wicri:cityArea></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Stem cells have been widely assumed to be capable of replacing lost or damaged cells in a number of diseases, including Parkinson's disease (PD), in which neurons of the substantia nigra (SN) die and fail to provide the neurotransmitter, dopamine (DA), to the striatum. We report that undifferentiated human neural stem cells (hNSCs) implanted into 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated Parkinsonian primates survived, migrated, and had a functional impact as assessed quantitatively by behavioral improvement in this DA-deficit model, in which Parkinsonian signs directly correlate to reduced DA levels. A small number of hNSC progeny differentiated into tyrosine hydroxylase (TH) and/or dopamine transporter (DAT) immunopositive cells, suggesting that the microenvironment within and around the lesioned adult host SN still permits development of a DA phenotype by responsive progenitor cells. A much larger number of hNSC-derived cells that did not express neuronal or DA markers was found arrayed along the persisting nigrostriatal path, juxtaposed with host cells. These hNSCs, which express DA-protective factors, were therefore well positioned to influence host TH+ cells and mediate other homeostatic adjustments, as reflected in a return to baseline endogenous neuronal number-to-size ratios, preservation of extant host nigrostriatal circuitry, and a normalizing effect on α-synuclein aggregation. We propose that multiple modes of reciprocal interaction between exogenous hNSCs and the pathological host milieu underlie the functional improvement observed in this model of PD.</p></div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Californie</li><li>Colorado</li><li>Connecticut</li><li>Massachusetts</li></region></list><tree><noCountry><name sortKey="Markakis, Eleni A" sort="Markakis, Eleni A" uniqKey="Markakis E" first="Eleni A." last="Markakis">Eleni A. Markakis</name><name sortKey="Redmond, D Eugene" sort="Redmond, D Eugene" uniqKey="Redmond D" first="D. Eugene" last="Redmond">D. Eugene Redmond</name></noCountry><country name="États-Unis"><region name="Colorado"><name sortKey="Bjugstad, Kimberly B" sort="Bjugstad, Kimberly B" uniqKey="Bjugstad K" first="Kimberly B." last="Bjugstad">Kimberly B. Bjugstad</name></region><name sortKey="Blanchard, Barbara C" sort="Blanchard, Barbara C" uniqKey="Blanchard B" first="Barbara C." last="Blanchard">Barbara C. Blanchard</name><name sortKey="Elsworth, John D" sort="Elsworth, John D" uniqKey="Elsworth J" first="John D." last="Elsworth">John D. Elsworth</name><name sortKey="Gonzalez, Rodolfo" sort="Gonzalez, Rodolfo" uniqKey="Gonzalez R" first="Rodolfo" last="Gonzalez">Rodolfo Gonzalez</name><name sortKey="Gonzalez, Rodolfo" sort="Gonzalez, Rodolfo" uniqKey="Gonzalez R" first="Rodolfo" last="Gonzalez">Rodolfo Gonzalez</name><name sortKey="Gu, Zezong" sort="Gu, Zezong" uniqKey="Gu Z" first="Zezong" last="Gu">Zezong Gu</name><name sortKey="Lipton, Stuart A" sort="Lipton, Stuart A" uniqKey="Lipton S" first="Stuart A." last="Lipton">Stuart A. Lipton</name><name sortKey="Ourednik, Jitka" sort="Ourednik, Jitka" uniqKey="Ourednik J" first="Jitka" last="Ourednik">Jitka Ourednik</name><name sortKey="Ourednik, Vaclav" sort="Ourednik, Vaclav" uniqKey="Ourednik V" first="Vaclav" last="Ourednik">Vaclav Ourednik</name><name sortKey="Parsons, Xuejun H" sort="Parsons, Xuejun H" uniqKey="Parsons X" first="Xuejun H." last="Parsons">Xuejun H. Parsons</name><name sortKey="Roth, Robert H" sort="Roth, Robert H" uniqKey="Roth R" first="Robert H." last="Roth">Robert H. Roth</name><name sortKey="Sidman, Richard L" sort="Sidman, Richard L" uniqKey="Sidman R" first="Richard L." last="Sidman">Richard L. Sidman</name><name sortKey="Sladek, John R" sort="Sladek, John R" uniqKey="Sladek J" first="John R." last="Sladek">John R. Sladek</name><name sortKey="Snyder, Evan Y" sort="Snyder, Evan Y" uniqKey="Snyder E" first="Evan Y." last="Snyder">Evan Y. Snyder</name><name sortKey="Snyder, Evan Y" sort="Snyder, Evan Y" uniqKey="Snyder E" first="Evan Y." last="Snyder">Evan Y. Snyder</name><name sortKey="Teng, Yang D" sort="Teng, Yang D" uniqKey="Teng Y" first="Yang D." last="Teng">Yang D. Teng</name><name sortKey="Wakeman, Dustin R" sort="Wakeman, Dustin R" uniqKey="Wakeman D" first="Dustin R." last="Wakeman">Dustin R. Wakeman</name><name sortKey="Wakeman, Dustin R" sort="Wakeman, Dustin R" uniqKey="Wakeman D" first="Dustin R." last="Wakeman">Dustin R. Wakeman</name></country><country name="Canada"><noRegion><name sortKey="Kim, Seung U" sort="Kim, Seung U" uniqKey="Kim S" first="Seung U." last="Kim">Seung U. Kim</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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