The inhibition of glycogen synthase kinase-3 (GSK-3) can induce neurogenesis, and the associated activation of Wnt/β-catenin signaling via GSK-3 inhibition may represent a means to promote motor function recovery following spinal cord injury (SCI) via increased astrocyte migration, reduced astrocyte apoptosis, and enhanced axonal growth. Herein, we assessed the effects of GSK-3 inhibition in vitro on the neurogenesis of ependymal stem/progenitor cells (epSPCs) resident in the mouse spinal cord and of human embryonic stem cell-derived neural progenitors (hESC-NPs) and human-induced pluripotent stem cell-derived neural progenitors (hiPSC-NPs) and in vivo on spinal cord tissue regeneration and motor activity after SCI. We report that the treatment of epSPCs and human pluripotent stem cell-derived neural progenitors (hPSC-NPs) with the GSK-3 inhibitor Ro3303544 activates β-catenin signaling and increases the expression of the bIII-tubulin neuronal marker; furthermore, the differentiation of Ro3303544-treated cells prompted an increase in the number of terminally differentiated neurons. Administration of a water-soluble, bioavailable form of this GSK-3 inhibitor (Ro3303544-Cl) in a severe SCI mouse model revealed the increased expression of bIII-tubulin in the injury epicenter. Treatment with Ro3303544-Cl increased survival of mature neuron types from the propriospinal tract (vGlut1, Parv) and raphe tract (5-HT), protein kinase C gamma-positive neurons, and GABAergic interneurons (GAD65/67) above the injury epicenter. Moreover, we observed higher numbers of newly born BrdU/DCX-positive neurons in Ro3303544-Cl-treated animal tissues, a reduced area delimited by astrocyte scar borders, and improved motor function. Based on this study, we believe that treating animals with epSPCs or hPSC-NPs in combination with Ro3303544-Cl deserves further investigation towards the development of a possible therapeutic strategy for SCI.

Department of Human Genetics Faculty of Medical Sciences University of Kragujevac Kragujevac Serbia

Department of Organic Chemistry University of Valencia 46100 Burjassot Spain

Department of Otolaryngology Head and Neck Surgery Harvard Medical School Boston MA USA

Eaton Peabody Laboratories Department of Otolaryngology Massachusetts Eye and Ear Boston MA USA

Institute of Experimental Medicine Department of Neuroregeneration Czech Academy of Sciences Prague Czech Republic

National Stem Cell Bank Valencia Node Biomolecular Resources Platform PRB3 ISCIII Research Center Principe Felipe C Eduardo Primo Yúfera 3 46012 Valencia Spain

Neuronal and Tissue Regeneration Lab Research Center Principe Felipe C Eduardo Primo Yufera 3 46012 Valencia Spain

Organic Molecules Lab Research Center Principe Felipe C Eduardo Primo Yufera 3 46012 Valencia Spain

Stem Cell Therapies in Neurodegenerative Diseases Lab Research Center Principe Felipe C Eduardo Primo Yufera 3 Valencia Spain

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The activation of dormant ependymal cells following spinal cord injury

Neurogenesis as a Tool for Spinal Cord Injury