Reinduced Wnt signaling limits regenerative potential of sensory axons in the spinal cord following conditioning lesion

Conditioning lesion of the peripheral branch of dorsal column axons is a well-known paradigm enabling the central branch to regenerate after injury to the spinal cord. However, only a small number of regenerating axons enter grafted substrates, and they do not grow beyond the lesion. We found that conditioning lesion induces, in addition to growth-stimulating genes, related to receptor tyrosine kinase (Ryk), a potent repulsive receptor for Wnts. Wnts are expressed around the site of spinal cord injury, and we found that grafted bone marrow stromal cells secreting the Wnt inhibitors secreted frizzled-related protein 2 or Wnt inhibitory factor 1 enhanced regeneration of the central branch after peripheral conditioning lesion. Furthermore, we found that Wnt4-expressing grafts caused dramatic long-range retraction of the injured central branch of conditioned dorsal root ganglion neurons. Macrophages accumulate along the path of receding axons but not around Wnt4-expressing cells, suggesting that the retraction of dorsal column axons is not a secondary effect of increased macrophages attracted by Wnt4. Therefore, Wnt-Ryk signaling is an inhibitory force co-induced with growth-stimulating factors after conditioning lesion. Overcoming Wnt inhibition may further enhance therapies being designed on the basis of the conditioning-lesion paradigm.