Abstract
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.
Highlights
ResultsSpinal cord injury (SCI) can prompt the loss of motor, sensory, and autonomic functions, while the limited levels of endogenous repair lead to poor functional recovery; various studies have highlighted the therapeutic potential of various types of stem/progenitor cells [21, 48, 53]
We investigated whether the treatment of neural precursors with a potent glycogen synthase kinase-3 (GSK-3) inhibitor (Ro3303544) could induce neurogenesis and/or the expression of neuronal markers in vitro and in vivo in mice with complete transection of the spinal cord
We report that Ro3303544 treatment causes a rapid and robust inhibition of GSK-3 that is followed by the induction of β-catenin expression and increased neurogenesis in vitro in ependymal stem/progenitor cells (epSPCs) and hPSC-NPs
Summary
ResultsSpinal cord injury (SCI) can prompt the loss of motor, sensory, and autonomic functions, while the limited levels of endogenous repair lead to poor functional recovery; various studies have highlighted the therapeutic potential of various types of stem/progenitor cells [21, 48, 53]. While some approaches employ the transplantation of neural stem/ progenitor cells into the injured spinal cord, other studies focus on the activation of endogenous regenerative machinery. We demonstrated the modulation of the inhibitory consequences of astrogliosis following the transplantation of human embryonic stem cell–derived neural progenitors (hESC-NPs), possibly through the secretion of protective factors and the activation of notch and JAK/STAT signaling, as a means to favor neurogenesis [21]. The activation of Wnt/β-catenin signaling via GSK-3 inhibition may represent a means to promote motor function recovery from SCI via increased astrocyte migration, reduced astrocyte apoptosis, and enhanced axonal growth [15, 18, 58, 59]
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