The Canonical Wnt Surrogate Agonist scFv-Dkk1c Ameliorates Spinal Cord Injury in Rats

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.