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Oncomodulin derived from regeneration-associated macrophages in dorsal root ganglia promotes axon regeneration in the spinal cord

Kwon, M.; Seo, Y.; Cho, H.; Choi, J.; Kim, H. S.; Oh, Y.; Kim, M.; Park, H. H.; Joe, E.-H.; Kwon, M.-H.; Kang, H. C.; Kim, B. G.

2021-12-28 neuroscience
10.1101/2021.12.28.474322 bioRxiv
Show abstract

Preconditioning nerve injury drives pro-regenerative perineuronal macrophage activation in dorsal root ganglia (DRG). The present study reports that oncomodulin (ONCM) is produced from the regeneration-associated macrophages (RAMs) and strongly influences regeneration of DRG sensory axons. Preconditioning injury upregulated ONCM in DRG macrophages in a CCR2 dependent manner. ONCM in macrophages was necessary to produce RAMs in the in vitro model of neuron-macrophage interaction and played an essential role in for preconditioning or CCL2-induced neurite outgrowth. ONCM potently increased neurite outgrowth in cultured DRG neurons by activating a distinct gene set, particularly neuropeptide-related genes. Increasing extracellularly secreted ONCM in DRGs sufficiently enhanced capacity of neurite outgrowth. To achieve sustained ONCM activity in vivo, recombinant ONCM was encapsulated by a reducible epsilon-poly(L-lysine)-nanogel (REPL-NG) system based on electrostatic interaction. Localized injection of REPL-NG/ONCM complex into DRGs achieved a remarkable long-range axonal regeneration beyond spinal cord lesion, surpassing the extent of the preconditioning effects.

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