Activation of Neurogenesis in Multipotent Stem Cells Cultured In Vitro and in the Spinal Cord Tissue After Severe Injury by Inhibition of Glycogen Synthase Kinase-3

Neurotherapeutics, 2021 · DOI: https://doi.org/10.1007/s13311-020-00928-0 · Published: September 30, 2020

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

This study investigates whether inhibiting GSK-3 can promote neurogenesis and improve motor function recovery after spinal cord injury (SCI). 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). The researchers treated mouse spinal cord stem cells and human stem cell-derived neural progenitors with a GSK-3 inhibitor (Ro3303544) in vitro. 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 In a mouse SCI model, they administered a water-soluble form of the inhibitor (Ro3303544-Cl), observing increased neuronal marker expression, enhanced neurogenesis, reduced astrocyte scar borders, and improved motor function. 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.

Study Duration

60 days

Participants

Female adult C57/BL6 (30–60 g) mice

Evidence Level

Not specified

Key Findings

1
Ro3303544 activates β-catenin signaling and increases the expression of the bIII-tubulin neuronal marker in vitro. 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
2
Ro3303544-Cl increases the expression of neuronal markers 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.
3
Ro3303544-Cl improved motor function in a mouse SCI model. 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.

Research Summary

This study assesses the effects of GSK-3 inhibition on neurogenesis both in vitro and in vivo following spinal cord injury (SCI). 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. The GSK-3 inhibitor Ro3303544 increases neuronal marker expression and promotes differentiation towards mature neurons in vitro. 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 In a mouse SCI model, Ro3303544-Cl enhances neurogenesis, reduces astrocyte scarring, and improves motor function. 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.

Practical Implications

Therapeutic Strategy for SCI

Combining epSPCs or hPSC-NPs with Ro3303544-Cl could be a therapeutic strategy for SCI. 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.

Modulation of Astrogliosis

GSK-3 inhibition may modulate astrogliosis and induce neurogenesis. The inhibition of GSK-3 signaling represents a promising means to modulate astrogliosis and induce neurogenesis [24, 72, 73] and may exert synergetic effects in SCI recovery when combined with neural precursor cell therapy [58].

Development of Effective Treatments

GSK-3 inhibitors may facilitate the development of effective treatments for spinal cord injuries. Overall, the administration of GSK-3 inhibitors may facilitate the development of an effective treatment for injuries, including spinal cord trauma [18].

Study Limitations

1
Lack of functional sensory evaluations to test allodynia and/or sensory recovery.
2
BrdU appears to label only a small fraction of DCX-positive cells.
3
Further studies will be required to assess the effects of treatment on nociceptive and/or mechanical stimuli.

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