HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Figure and Table All Versions of this Article: 2005-0518v1 24/8/1976    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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Yan, J. Articles by Koliatsos, V. E. Search for Related Content PubMed PubMed Citation Articles by Yan, J. Articles by Koliatsos, V. E.

TRANSLATIONAL AND CLINICAL RESEARCH

Combined Immunosuppressive Agents or CD4 Antibodies Prolong Survival of Human Neural Stem Cell Grafts and Improve Disease Outcomes in Amyotrophic Lateral Sclerosis Transgenic Mice

^aDepartment of Pathology, Division of Neuropathology, and Departments of
^bNeurology,
^cNeuroscience, and
^dPsychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA;
^eNeuralStem, Inc., Gaithersburg, Maryland, USA

Key Words. Differentiation • Motor neuron disease • Motor neurons • Regeneration • Superoxide dismutase

Correspondence: Vassilis E. Koliatsos, M.D., The Johns Hopkins University School of Medicine, Neuropathology Division, Ross Building, Room 558, 720 Rutland Avenue, Baltimore, Maryland 21205, USA. Telephone: 410-502-5191; Fax: 410-955-9777; e-mail: koliat{at}jhmi.edu

Received on October 18, 2005; accepted for publication on April 10, 2006.

First published online in STEM CELLS EXPRESS  April 27, 2006.


Amyotrophic lateral sclerosis (ALS) is a target for cell-replacement therapies, including therapies based on human neural stem cells (NSCs). These therapies must be first tested in the appropriate animal models, including transgenic rodents harboring superoxide dismutase (SOD1) mutations linked to familial ALS. However, these rodent subjects reject discordant xenografts. In the present investigation, we grafted NSCs from human embryonic spinal cord into the ventral lumbar cord of 2-month-old SOD1-G93A transgenic mice. Animals were immunosuppressed with FK506, FK506 plus rapamycin, FK506 plus rapamycin plus mycophenolate mofetil, or CD4 antibodies. With FK506 monotherapy, human NSC grafts were rejected within 1 week, whereas combinations of FK506 with one or two of the other agents or CD4 antibodies protected grafts into end-stage illness (i.e., more than 2 months after grafting). The combination of FK506 with rapamycin appeared to be optimal with respect to efficacy and simplicity of administration. Graft protection was achieved via the blockade of CD4- and CD8-cell infiltration and attenuation of the microglial phagocytic response from the host. Surviving NSCs differentiated extensively into neurons that began to establish networks with host nerve cells, including -motor neurons. Immunosuppressed animals with live cells showed later onset and a slower progression of motor neuron disease and lived longer compared with immunosuppressed control animals with dead NSC grafts. Our findings indicate that combined immunosuppression promotes the survival of human NSCs grafted in the spinal cord of SOD1-G93A mice and, in doing so, allows the differentiation of NSCs into neurons and leads to the improvement of key parameters of motor neuron disease.

This article has been cited by other articles:

				S. J. Greco, K. Liu, and P. Rameshwar Functional Similarities Among Genes Regulated by Oct4 in Human Mesenchymal and Embryonic Stem Cells Stem Cells, December 1, 2007; 25(12): 3143 - 3154. [Abstract] [Full Text] [PDF]

				S. J. Greco, S. V. Smirnov, R. G. Murthy, and P. Rameshwar Synergy between the RE-1 Silencer of Transcription and NF{kappa}B in the Repression of the Neurotransmitter Gene TAC1 in Human Mesenchymal Stem Cells J. Biol. Chem., October 12, 2007; 282(41): 30039 - 30050. [Abstract] [Full Text] [PDF]

				S. Corti, F. Locatelli, D. Papadimitriou, R. Del Bo, M. Nizzardo, M. Nardini, C. Donadoni, S. Salani, F. Fortunato, S. Strazzer, et al. Neural stem cells LewisX + CXCR4 + modify disease progression in an amyotrophic lateral sclerosis model Brain, May 1, 2007; 130(5): 1289 - 1305. [Abstract] [Full Text] [PDF]