FM19G11 Favors Spinal Cord Injury Regeneration and Stem Cell Self-Renewal by Mitochondrial Uncoupling and Glucose Metabolism Induction

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