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FM19G11 favors spinal cord injury regeneration and stem cell self-renewal by mitochondrial uncoupling and glucose metabolism induction

AutorRodríguez-Jiménez, Francisco Javier; Alastrue-Agudo, Ana; Erceg, Slaven; Stojkovic, Miodrag; Moreno-Manzano, Victoria
Palabras claveSpinal cord regeneration
Glucose metabolism
Ependymal stem cells
Fecha de publicación20-sep-2012
EditorJohn Wiley & Sons
CitaciónStem Cells 30(10): 2221-2233 (2012)
ResumenSpinal 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. © AlphaMed Press.
Versión del editorhttp://dx.doi.org/10.1002/stem.1189
Identificadoresissn: 1066-5099
e-issn: 1549-4918
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