authors contributed equally.
Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates†
Article first published online: 11 MAY 2009
Copyright © 2009 American Neurological Association
Annals of Neurology
Volume 66, Issue 3, pages 343–354, September 2009
How to Cite
Pluchino, S., Gritti, A., Blezer, E., Amadio, S., Brambilla, E., Borsellino, G., Cossetti, C., Del Carro, U., Comi, G., 't Hart, B., Vescovi, A. and Martino, G. (2009), Human neural stem cells ameliorate autoimmune encephalomyelitis in non-human primates. Ann Neurol., 66: 343–354. doi: 10.1002/ana.21745
Potential conflict of interest: Nothing to report.
- Issue published online: 1 OCT 2009
- Article first published online: 11 MAY 2009
- Accepted manuscript online: 11 MAY 2009 12:00AM EST
- Manuscript Accepted: 1 MAY 2009
- Manuscript Revised: 9 APR 2009
- Manuscript Received: 3 JAN 2009
- European Union–funded framework program 5. Grant Number: HPRI-CT-2001-00150
- Italian Multiple Sclerosis Foundation. Grant Numbers: 2004/R/15, 2002/R/37, 2002/R/33, 2002/B/11 rif. 2002/R/37
- National Multiple Sclerosis Society. Grant Numbers: RG-4001-A1, RG 3591-A-1, RG 3762-A-1
- Italian Ministry of Research and University
- Italian Ministry of Health. Grant Numbers: CS 118.1, RF03.168
- Italian Superior Institute of Health. Grant Number: # ISS CS118
- BMW Italy Group. Grant Number: BMW 2008 MART
- Myelin Project and Banca Agricola Popolare di Ragusa
- Fundação para a Ciência e a Tecnologia. Grant Number: SFRH/BD/15899/2005
Transplanted neural stem/precursor cells (NPCs) display peculiar therapeutic plasticity in vivo. Although the replacement of cells was first expected as the prime therapeutic mechanism of stem cells in regenerative medicine, it is now clear that transplanted NPCs simultaneously instruct several therapeutic mechanisms, among which replacement of cells might not necessarily prevail. A comprehensive understanding of the mechanism(s) by which NPCs exert their therapeutic plasticity is lacking. This study was designed as a preclinical approach to test the feasibility of human NPC transplantation in an outbreed nonhuman primate experimental autoimmune encephalomyelitis (EAE) model approximating the clinical and complex neuropathological situation of human multiple sclerosis (MS) more closely than EAE in the standard laboratory rodent.
We examined the safety and efficacy of the intravenous (IV) and intrathecal (IT) administration of human NPCs in common marmosets affected by human myelin oligodendrocyte glycoprotein 1-125–induced EAE. Treatment commenced upon the occurrence of detectable brain lesions on a 4.7T spectrometer.
EAE marmosets injected IV or IT with NPCs accumulated lower disability and displayed increased survival, as compared with sham-treated controls. Transplanted NPCs persisted within the host central nervous system (CNS), but were also found in draining lymph nodes, for up to 3 months after transplantation and exhibited remarkable immune regulatory capacity in vitro.
Herein, we provide the first evidence that human CNS stem cells ameliorate EAE in nonhuman primates without overt side effects. Immune regulation (rather than neural differentiation) is suggested as the major putative mechanism by which NPCs ameliorate EAE in vivo. Our findings represent a critical step toward the clinical use of human NPCs in MS. Ann Neurol 2009;66:343–354