title: FM19G11 favors spinal cord injury regeneration and stem cell self-renewal by mitochondrial uncoupling and glucose metabolism induction.
abstract: 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.
authors.affiliation: Neuronal Regeneration Lab, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Rodríguez-Jimnez
authors.forename: Ana
authors.initials: A
authors.lastname: Alastrue-Agudo
authors.forename: Slaven
authors.initials: S
authors.lastname: Erceg
authors.forename: Miodrag
authors.initials: M
authors.lastname: Stojkovic
authors.forename: Victoria
authors.initials: V
authors.lastname: Moreno-Manzano
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000037:antagonists & inhibitors / Q000235:genetics; D053687:Adult Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D004805:Ependyma / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000037:antagonists & inhibitors / Q000235:genetics; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D009416:Nerve Regeneration / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013119:Spinal Cord Injuries / Q000473:pathology / Q000628:therapy*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2
chemical_list: D001549:Benzamides; C555528:FM19G11; D051275:Glucose Transporter Type 4; D007473:Ion Channels; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase; D005947:Glucose