Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells
- D. Eugene Redmond, Jr.*,†,‡,
- Kimberly B. Bjugstad§,
- Yang D. Teng¶,
- Vaclav Ourednik¶,‖,
- Jitka Ourednik¶,‖,
- Dustin R. Wakeman**,††,
- Xuejun H. Parsons**,
- Rodolfo Gonzalez**,††,
- Barbara C. Blanchard§,
- Seung U. Kim‡‡,
- Zezong Gu**,
- Stuart A. Lipton**,
- Eleni A. Markakis*,
- Robert H. Roth*,§§,
- John D. Elsworth*,§§,
- John R. Sladek, Jr.§,¶¶,
- Richard L. Sidman‡,¶, and
- Evan Y. Snyder‡,¶,**
- Departments of *Psychiatry,
- †Neurosurgery, and
- §§Pharmacology, Yale University School of Medicine, New Haven, CT 06510;
- §Department of Psychiatry, University of Colorado, Aurora, CO 80045;
- ¶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;
- **Burnham Institute for Medical Research, La Jolla, CA 92037;
- ‡‡Department of Neurology, University of British Columbia, Vancouver, BC, Canada V6T 2B5; and
- ††Biomedical Sciences and Molecular Pathology Programs, University of California at San Diego, La Jolla, CA 92093
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Contributed by Richard L. Sidman, May 2, 2007 (received for review March 6, 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.
Footnotes
- ‡To whom correspondence may be addressed. E-mail: eugene.redmond{at}yale.edu, richard_sidman{at}hms.harvard.edu, or esnyder{at}burnham.org
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Author contributions: D.E.R., K.B.B., Y.D.T., and V.O. contributed equally to this work; D.E.R., Y.D.T., V.O., R.H.R., J.D.E., J.R.S., R.L.S., and E.Y.S. designed research; D.E.R., K.B.B., Y.D.T., V.O., J.O., D.R.W., X.H.P., R.G., B.C.B., Z.G., S.A.L., E.A.M., J.D.E., and E.Y.S. performed research; S.U.K. contributed new reagents/analytic tools; D.E.R., K.B.B., Y.D.T., V.O., J.O., D.R.W., X.H.P., R.G., B.C.B., Z.G., S.A.L., E.A.M., R.H.R., J.D.E., J.R.S., R.L.S., and E.Y.S. analyzed data; and D.E.R., K.B.B., Y.D.T., R.L.S., and E.Y.S. wrote the paper.
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↵ ‖Present address: Laboratory of CNS Development, Regeneration, and Neurotransplantation, Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA 50011-1250.
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↵ ¶¶Present address: Department of Biology, California Lutheran University, 60 West Olsen Road, Thousand Oaks, CA 91360.
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The authors declare no conflict of interest.
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See Commentary on page 11869.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0704091104/DC1.
- Abbreviations:
- DA,
- dopamine;
- DAT,
- dopamine transporter;
- hNSC,
- human neural stem cell;
- ir,
- immunoreactive;
- MPTP,
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;
- PD,
- Parkinson's disease;
- SN,
- substantia nigra;
- TH,
- tyrosine hydroxylase;
- PFS,
- Parkinson's factor score;
- GDNF,
- glial cell line-derived neurotrophic factor;
- NuMa,
- nuclear mitotic apparatus.
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Freely available online through the PNAS open access option.
- © 2007 by The National Academy of Sciences of the USA
