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Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons

Nature Biotechnology volume 20, pages 1103–1110 (2002)Cite this article

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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Figure 1: Effect of MPTP treatment on TH expression and the total number of neurons in SN (pars compacta and lateralis) and VTA in nongrafted mice.
Figure 2: (A,B) Analysis of D-amphetamine-evoked rotational behavior in MPTP-treated and grafted animals.
Figure 3: TH expression in mesencephalon and striatum of aged mice following MPTP lesioning and unilateral NSC engraftment into the SN/VTA area.
Figure 4: Quantification of TH+ cells in nigral (A, B) and ectopic (C, D) brainstem regions of both hemispheres in mock-grafted (sham) and NSC-grafted MPTP-lesioned animals.
Figure 5: Immunohistochemical analyses of TH+, DAT+, and BrdU+ cells in MPTP-treated and grafted mouse brains.
Figure 6: Rescued TH+ neurons in the SN/VTA of a transplanted female mouse are shown to be unambiguously of pre-existent host origin by demonstrating the presence of Barr bodies in their nuclei.
Figure 7: Grafted NSCs, in their undifferentiated state, intrinsically express GDNF in and adjacent to areas containing rescued host DA neurons.

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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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Author notes

  1. Jitka Ourednik and Václav Ourednik: These authors contributed equally to this work.

  2. Melitta Schachner and Evan Y. Snyder: These authors, ordered alphabetically, contributed equally to this work.

Authors and Affiliations

  1. Department of Neurobiology, Swiss Federal Institute of Technology, Hoenggerberg, CH-8093, Switzerland

    Jitka Ourednik, Václav Ourednik & Melitta Schachner

  2. Department of Neurology, Harvard Medical School, Harvard Institutes of Medicine, Boston, 02115, MA, USA

    Jitka Ourednik, Václav Ourednik & Evan Y. Snyder

  3. Department of Microbiology/Immunology, Northeastern Ohio Universities College of Medicine, Rootstown, 44272, OH, USA

    William P. Lynch

  4. Center for Molecular Neurobiology Hamburg, University of Hamburg, Martinistrasse 52, Hamburg, 20246, Germany

    Melitta Schachner

  5. Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, 50011, IA, USA

    Jitka Ourednik & Václav Ourednik

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Correspondence to Jitka Ourednik or Evan Y. Snyder.

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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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