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Preclinical evaluation of adult stem cell engraftment and toxicity in the CNS of rhesus macaques

Academic Article
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Overview

authors

  • Isakova, L. A.
  • Baker, K.
  • Dufour, J.
  • Gaupp, D.
  • Phinney, Donald

publication date

  • 2006

journal

  • Molecular Therapy  Journal

abstract

  • Congenital neurodegenerative diseases exhibit progressive postnatal neurologic impairment leading to premature death and are intractable to systemic therapies such as bone marrow transplantation. We injected bone marrow-derived mesenchymal stem cells (MSCs) into the CNS of young adult rhesus macaques to evaluate their safety and feasibility as vectors for direct intervention of neurologic disorders. Levels of engrafted male, donor MSCs were quantified in the CNS of female transplant recipients by real-time PCR using an SRY gene-specific probe. Analysis of coronal brain slices encompassing one-third of the total brain volume revealed engraftment levels ranging from 0.026 x 10(-3) to 0.163 x 10(-3)% of the total DNA content of brain tissue. Fine-mapping revealed male DNA distributed within specific anatomic structures along the neuraxis where label-retaining MSCs were visualized in histological sections by immunohistochemistry. Double labeling of sections confirmed that engrafted donor cells lacked expression of the macrophage marker CD68, the astrocytes marker GFAP, and neuronal markers NeuN and MAP2. MSC engraftment had no adverse effects on animal health, behavior, postural and locomotor patterns, or upper limb motor performance evaluated over a 6-month period posttransplantation. Therefore, MSC-based therapies represent a safe alternative for clinical intervention of CNS disorders.

subject areas

  • Age Factors
  • Animals
  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Antigens, Nuclear
  • Behavior, Animal
  • Biomarkers
  • Bone Marrow Transplantation
  • Brain
  • Cell Differentiation
  • Central Nervous System
  • Drug Evaluation, Preclinical
  • Female
  • Macaca mulatta
  • Male
  • Microtubule-Associated Proteins
  • Motor Activity
  • Nerve Tissue Proteins
  • Polymerase Chain Reaction
  • Sex-Determining Region Y Protein
  • Stem Cell Transplantation
  • Toxicity Tests
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Research

keywords

  • lysosomal storage disease
  • mesenchymal stem cells
  • motor performance
  • real-time PCR
  • rhesus macaques
  • spontaneous behavior
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Identity

International Standard Serial Number (ISSN)

  • 1525-0016

Digital Object Identifier (DOI)

  • 10.1016/j.ymthe.2005.12.014

PubMed ID

  • 16497561
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Additional Document Info

start page

  • 1173

end page

  • 1184

volume

  • 13

issue

  • 6

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