Neural stem cells display an inherent mechanism for rescuing dysfunctional neurons

Nat Biotechnol. 2002 Nov;20(11):1103-10. doi: 10.1038/nbt750. Epub 2002 Oct 15.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / administration & dosage
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / analogs & derivatives*
  • Aging
  • Animals
  • Cell Count
  • Cell Survival
  • Dextroamphetamine / pharmacology
  • Female
  • MPTP Poisoning / pathology
  • MPTP Poisoning / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Regeneration / physiology*
  • Neurons / drug effects
  • Neurons / pathology*
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / pathology*
  • Parkinsonian Disorders / physiopathology*
  • Parkinsonian Disorders / surgery
  • Recovery of Function
  • Reference Values
  • Signal Transduction
  • Stem Cell Transplantation*
  • Stem Cells / drug effects
  • Stem Cells / pathology
  • Stem Cells / physiology
  • Substantia Nigra / drug effects
  • Substantia Nigra / pathology
  • Substantia Nigra / physiopathology*
  • Substantia Nigra / surgery
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Tyrosine 3-Monooxygenase
  • Dextroamphetamine