Abstract
We investigated the hypothesis that neural stem cells (NSCs) possess an intrinsic capacity to “rescue” dysfunctional neurons in the brains of aged mice. The study focused on a neuronal cell type with stereotypical projections that is commonly compromised in the aged brain—the dopaminergic (DA) neuron. Unilateral implantation of murine NSCs into the midbrains of aged mice, in which the presence of stably impaired but nonapoptotic DA neurons was increased by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was associated with bilateral reconstitution of the mesostriatal system. Functional assays paralleled the spatiotemporal recovery of tyrosine hydroxylase (TH) and dopamine transporter (DAT) activity, which, in turn, mirrored the spatiotemporal distribution of donor-derived cells. Although spontaneous conversion of donor NSCs to TH+ cells contributed to nigral reconstitution in DA-depleted areas, the majority of DA neurons in the mesostriatal system were “rescued” host cells. Undifferentiated donor progenitors spontaneously expressing neuroprotective substances provided a plausible molecular basis for this finding. These observations suggest that host structures may benefit not only from NSC-derived replacement of lost neurons but also from the “chaperone” effect of some NSC-derived progeny.
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Acknowledgements
We thank Tom Yang and Wesley Brooks for their gift of the Barr body–specific immune serum and Mahesh Lachyankar in the Snyder laboratory for sharing unpublished data. We also thank Yvonne Bruderer and Markus Rimann for technical assistance, Kathrin Mannigel for maintenance of the animal colony, and Donald E. Mitchell, Olga Kukal, and Tom Allen for input. This work was supported in part by grants from the Swiss National Research Foundation to M.S., the Michael J. Fox/Parkinson Action Network to V.O., the International Institute for Research in Paraplegia, Zurich, to V.O. and E.Y.S., National Institutes of Neurological Diseases and Stroke, the A-T Children's Project, March of Dimes, Project ALS and the International Organization for Glutaric Acidemia to E.Y.S.
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Ourednik, J., Ourednik, V., Lynch, W. et al. Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons. Nat Biotechnol 20, 1103–1110 (2002). https://doi.org/10.1038/nbt750
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DOI: https://doi.org/10.1038/nbt750
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