Age and Dose-Related Effects on MSC Engraftment Levels and Anatomical Distribution in the CNS of Non-Human Primates: Identification of Novel MSC Subpopulations that Respond to Guidance Cues in Brain

¹ Center for Gene Therapy, Tulane University Health Science Center, New Orleans, LA
² Department of Veterinary Medicine, Tulane National Research Primate Center, Covington, LA.

^* To whom correspondence should be addressed. E-mail: dphinne{at}tulane.edu.

	Abstract

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 CNS of adult rhesus macaques engrafted at low levels without adversely effecting 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 PCR 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 to that reported previously for young adult macaques. Moreover, engraftment levels were 30-fold higher after injection of a low vs. high cell dose and engrafted MSCs were non-randomly 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 six 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.