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This Article Free via Open Access: OA OA Full Text Full Text (PDF) Supplemental Data OA All Versions of this Article: 2007-0543v1 25/12/3261    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Isakova, I. A. Articles by Phinney, D. G. Search for Related Content PubMed PubMed Citation Articles by Isakova, I. A. Articles by Phinney, D. G.

TRANSLATIONAL AND CLINICAL RESEARCH

Age- and Dose-Related Effects on MSC Engraftment Levels and Anatomical Distribution in the Central Nervous Systems of Nonhuman Primates: Identification of Novel MSC Subpopulations That Respond to Guidance Cues in Brain

^aCenter for Gene Therapy, Tulane University Health Science Center, New Orleans, Louisiana, USA;
^bDepartment of Veterinary Medicine, Tulane National Primate Research Center, Covington, Louisiana, USA

Key Words. Mesenchymal stem cells • Rhesus macaques • Real-time polymerase chain reaction • Guidance receptors • Chemotaxis Neurodegenerative diseases

Correspondence: Donald G. Phinney, Ph.D., SL-99, Center for Gene Therapy, Tulane University Health Sciences Center, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA. Telephone: (504) 988-7725; Fax: (504) 988-7710; e-mail: dphinne{at}tulane.edu

Received July 9, 2007; accepted for publication October 2, 2007.
First published online in STEM CELLS EXPRESS   October 11, 2007.



Mesenchymal stem cells (MSCs) have demonstrated efficacy as therapeutic vectors in rodent models of neurological diseases, but few studies have evaluated their safety and efficacy in a relevant large animal model. Previously, we reported that MSCs transplanted to the central nervous systems (CNS) of adult rhesus macaques engrafted at low levels without adversely affecting animal health, behavior, or motor function. Herein, we injected MSCs intracranially into 10 healthy infant macaques and quantified their engraftment levels and mapped their anatomical distribution in brain by real-time polymerase chain reaction using an sry gene-specific probe. These analyses revealed that MSC engraftment levels in brain were on average 18-fold higher with a maximal observed difference of 180-fold in neonates as compared with that reported previously for young adult macaques. Moreover, engraftment levels were 30-fold higher after injection of a low versus high cell dose and engrafted MSCs were nonrandomly distributed throughout the infant brain and localized to specific anatomical regions. Identification of unique subpopulations of macaque and human MSCs that express receptor proteins known to regulate tangential migration of interneurons may explain their migration patterns in brain. Extensive monitoring of infant transplant recipients using a battery of age appropriate tests found no evidence of any long-term adverse effects on the health or social, behavioral, cognitive, or motor abilities of animals up to 6 months post-transplant. Therefore, direct intracranial injection represents a safe means to deliver therapeutic levels of MSCs to the CNS. Moreover, expressed guidance receptors on MSC subpopulations may regulate migration of cells in the host brain.

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