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Article first published online: 20 SEP 2012
Copyright © 2012 AlphaMed Press
Volume 30, Issue 10, pages 2221–2233, October 2012
How to Cite
Rodríguez-Jiménez, F. J., Alastrue-Agudo, A., Erceg, S., Stojkovic, M. and Moreno-Manzano, V. (2012), FM19G11 Favors Spinal Cord Injury Regeneration and Stem Cell Self-Renewal by Mitochondrial Uncoupling and Glucose Metabolism Induction. STEM CELLS, 30: 2221–2233. doi: 10.1002/stem.1189
Author contributions: F.J.R.J., M.S, and V.M.M: Conceived and designed the experiments; V.M.M and M.S.: Financial support to perform the work; F.J.R.J., A.A.A, S.E., and V.M.M: Performed the experiments; F.J.R.J. and V.M.M., Wrote the paper and conceived and designed the experiments.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS August 3, 2012.
- Issue published online: 20 SEP 2012
- Article first published online: 20 SEP 2012
- Accepted manuscript online: 3 AUG 2012 02:24PM EST
- Manuscript Accepted: 22 JUN 2012
- Manuscript Received: 19 APR 2012
- Spinal cord regeneration;
- Glucose metabolism;
- Ependymal stem cells;
Spinal cord injury is a major cause of paralysis with no currently effective therapies. Induction of self-renewal and proliferation of endogenous regenerative machinery with noninvasive and nontoxic therapies could constitute a real hope and an alternative to cell transplantation for spinal cord injury patients. We previously showed that FM19G11 promotes differentiation of adult spinal cord-derived ependymal stem cells under hypoxia. Interestingly, FM19G11 induces self-renewal of these ependymal stem cells grown under normoxia. The analysis of the mechanism of action revealed an early increment of mitochondrial uncoupling protein 1 and 2 with an early drop of ATP, followed by a subsequent compensatory recovery with activated mitochondrial metabolism and the induction of glucose uptake by upregulation of the glucose transporter GLUT-4. Here we show that phosphorylation of AKT and AMP-activated kinase (AMPK) is involved in FM19G11-dependent activation of GLUT-4, glucose influx, and consequently in stem cell self-renewal. Small interfering RNA of uncoupling protein 1/2, GLUT-4 and pharmacological inhibitors of AKT, mTOR and AMPK signaling blocked the FM19G11-dependent induction of the self-renewal-related markers Sox2, Oct4, and Notch1. Importantly, FM19G11-treated animals showed accelerated locomotor recovery. In vivo intrathecal sustained administration of FM19G11 in rats after spinal cord injury showed more neurofilament TUJ1-positive fibers crossing the injured area surrounded by an increase of neural precursor Vimentin-positive cells. Overall, FM19G11 exerts an important influence on the self-renewal of ependymal stem progenitor cells with a plausible neuroprotective role, providing functional benefits for spinal cord injury treatment. STEM Cells2012;30:2221–2233