The Canonical Wnt Surrogate Agonist scFv-Dkk1c Ameliorates Spinal Cord Injury in Rats
Pau González1,2, Alfredo Maqueda3,4, Carlos González-Fernández3,4
1Laboratory of Molecular Neurology, Hospital Nacional de Parapléjicos, SESCAM, Carretera Finca La Peraleda S/N, 45071, Toledo, Spain. paug@sescam.jccm.es.
Abstract:
Despite the therapeutic potential of canonical Wnt/β-catenin signaling activation in spinal cord injury (SCI), the development of Wnt-based therapeutic approaches is severely hampered by difficulties in Wnt ligand production, their high receptor cross-reactivity and the unspecificity of glycogen synthase kinase-3β inhibitors. Consequently, the generation of chimeric canonical Wnt surrogates that can overcome the previously detailed limitations has been of paramount importance for the development of Wnt-based therapeutic approaches, although their potential beneficial role in SCI has not been assessed to date. For this purpose, we have evaluated the effects exerted by the overexpression of the canonical Wnt surrogate scFv-Dkk1c in a clinically relevant model of SCI in critical injury-related aspects such as motor functional recovery, myelin preservation/loss, neuronal cell density, microglia/macrophage and astroglial reactivity, expression of markers related to astroglial and microglia/macrophage polarization, vascularization and descending serotonergic innervation. Briefly, we found that scFv-Dkk1c overexpression during the progression of SCI significantly improved motor functional recovery concomitant with changes in the SCI-associated microglia/macrophage reactivity, expression of markers related to microglia/macrophage polarization, astroglial reactivity and tissue vascularization, without affecting myelin preservation/loss, neuronal cell density, expression of markers related to astroglial polarization, NG2 + cell presence and descending serotonergic innervation. In conclusion, the present study provides experimental evidence for the potential role of the canonical Wnt surrogate scFv-Dkk1c in the context of SCI.
Insights
This study introduces scFv-Dkk1c, a novel Wnt surrogate, demonstrating its potential to improve motor function recovery after spinal cord injury (SCI). The findings highlight its therapeutic promise for SCI by modulating inflammatory and vascular responses.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Biotechnology
Background:
- Canonical Wnt/β-catenin signaling holds therapeutic promise for spinal cord injury (SCI).
- Current Wnt-based therapies face challenges including Wnt ligand production, receptor cross-reactivity, and GSK-3β inhibitor specificity.
- Development of Wnt surrogates is crucial for advancing Wnt-based SCI therapeutics.
Purpose of the Study:
- To evaluate the therapeutic potential of the Wnt surrogate scFv-Dkk1c in a preclinical model of SCI.
- To assess scFv-Dkk1c's effects on motor functional recovery, tissue preservation, and cellular responses post-SCI.
Main Methods:
- Overexpression of scFv-Dkk1c in a clinically relevant SCI model.
- Assessment of motor function, myelin preservation, neuronal density, and glial/immune cell reactivity.
- Analysis of vascularization and specific cellular markers related to inflammation and regeneration.
Main Results:
- scFv-Dkk1c overexpression significantly improved motor functional recovery in SCI.
- Observed modulation of microglia/macrophage and astroglial reactivity and polarization markers.
- Enhanced tissue vascularization was noted, without impacting myelin, neuronal density, or serotonergic innervation.
Conclusions:
- The canonical Wnt surrogate scFv-Dkk1c demonstrates significant therapeutic potential for spinal cord injury.
- scFv-Dkk1c favorably influences motor recovery and neuroinflammatory/vascular aspects of SCI.
- Further research into scFv-Dkk1c is warranted for developing novel SCI treatments.
