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Cross-Talk Between Stem Cells and the Dysfunctional Brain is Facilitated by Manipulating the Niche: Evidence from an Adhesion Molecule†‡§

  1. Václav Ourednik2,3,
  2. Jitka Ourednik2,3,
  3. Yifang Xu2,
  4. Ying Zhang2,
  5. William P. Lynch4,
  6. Evan Y. Snyder1,3,¶,*,
  7. Melitta Schachner5,6,‖,*

Article first published online: 25 SEP 2009

DOI: 10.1002/stem.227

Issue

STEM CELLS

STEM CELLS

Volume 27, Issue 11, pages 2846–2856, November 2009

Additional Information

How to Cite

Ourednik, V., Ourednik, J., Xu, Y., Zhang, Y., Lynch, W. P., Snyder, E. Y. and Schachner, M. (2009), Cross-Talk Between Stem Cells and the Dysfunctional Brain is Facilitated by Manipulating the Niche: Evidence from an Adhesion Molecule. STEM CELLS, 27: 2846–2856. doi: 10.1002/stem.227

Author Information

  1. 1

    Burnham Institute for Medical Research, La Jolla, California

  2. 2

    Department of Biomedical Sciences, VetMed, Iowa State University, Ames, Iowa

  3. 3

    Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

  4. 4

    Department of Microbiology/Immunology, Northeastern Ohio Universities Colleges of Medicine, Rootstown, Ohio

  5. 5

    Zentrum für Molekulare Neurobiologie, University Hospital Hamburg-Eppendorf, Hamburg, Germany

  6. 6

    W.M. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey

  1. Telephone: 858-646-3158; Fax: 858-713-6273

  2. ‖

    Telephone: 732-445-2061; Fax: 732-445-2063

*Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA

  1. †

    Author contributions: V.O., J.O.: designed and executed the experiments, gathered and interpreted the data, wrote the manuscript; Y.X., Y.Z.: performed the experiments and gathered data; W.P.L.: designed and performed the experiments, gathered and interpreted data, and edited the manuscript; E.Y.S., M.S.: designed the experiments, interpreted the results, wrote the manuscript, and provided overall supervision and financial support.

  2. ‡

    Disclosure of potential conflicts of interest is found at the end of this article.

  3. §

    First published online in STEM CELLS EXPRESS September 25, 2009.

  4. Telephone: 858-646-3158; Fax: 858-713-6273

  5. ‖

    Telephone: 732-445-2061; Fax: 732-445-2063

Publication History

  1. Issue published online: 6 NOV 2009
  2. Article first published online: 25 SEP 2009
  3. Accepted manuscript online: 25 SEP 2009 12:00AM EST
  4. Manuscript Accepted: 8 AUG 2009
  5. Manuscript Received: 1 APR 2008

Funded by

  • NIGMS. Grant Number: P20 GM075059
  • American Parkinson's Disease Association
  • Sanford Children's Health Research Center
  • A-T Children's Project
  • Project ALS
  • Children's Neurobiological Solutions
  • International Organization for Glutaric Acidemia
  • Minneapolis Jewish Foundation; Margot Anderson Brain Restoration Foundation

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Keywords:

  • aging;
  • astrocytes;
  • differentiation;
  • dopamine;
  • L1;
  • migration;
  • mouse model;
  • MPTP;
  • neurodegeneration;
  • Parkinson's disease;
  • transplantation;
  • chaperone effect;
  • neuroprotection;
  • adhesion molecule;
  • extracellular matrix;
  • aging and age-related diseases;
  • niche;
  • neural stem cells

Abstract

In the injured brain, the behavior of neural stem/progenitor cells (NSCs) is regulated by multiple converging factors encountered in the niche, which is composed of several neural and non-neural cell types. Signals emanating from the host influence the migration, survival, distribution, and fate of transplanted NSCs, which in turn can create host microenvironments that favor a return to homeostasis. We tested the hypothesis that overexpression of key facilitatory molecules that define the injury niche might enhance this bidirectional stem cell–host interaction to therapeutic advantage. As proof of concept, we investigated whether conditioning the niche with the neural cell adhesion molecule L1 might enhance recovery in a prototypical neurodegenerative milieu—the MPTP-induced model of Parkinson's disease in aged mice—where cross-talk between NSCs and imperiled host dopaminergic neurons is known to be pivotal in rescuing the function and connectivity of the latter. In lesioned mice (and in unlesioned controls), we overexpressed L1 in the NSCs to be transplanted into the ventral mesencephalon. Several pairwise experimental combinations were tested based on variations of engrafting L1 overexpressing versus nonoverexpressing NSCs into wild-type (WT) versus L1-overexpressing transgenic mice (specifically L1 transcribed from the GFAP promoter and, hence, overexpressed in host astrocytes). Enrichment for L1—particularly when expressed simultaneously in both donor NSCs and host brain—led to rapid and extensive distribution of exogenous NSCs, which in turn rescued (with an efficacy greater than in nonengineered controls) dysfunctional host dopaminergic nigral neurons, even when grafting was delayed by a month. L1 overexpression by NSCs also enhanced their own differentiation into tyrosine hydroxylase–expressing neurons in both WT and transgenic hosts. Graft–host interactions were thus favored by progressively increasing levels of L1. More broadly, this study supports the view that manipulating components of the niche (such as an adhesion molecule) that facilitate cross-talk between stem cells and the dysfunctional brain may offer new strategies for more efficacious neurotransplantation, particularly when treatment is delayed as in chronic lesions or advanced stages of a neurodegenerative disease. STEM CELLS 2009;27:2846–2856

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