Sensory nerve input is not required for digit tip regeneration

Peripheral nerves are a major component of the post-injury microenvironment and are required for successful appendage regeneration in non-mammalians. However, the role of innervation in mouse digit tip regeneration is unclear. We developed a denervation technique that maintains mechanical loading while significantly reducing innervation to the digit. Using this model, we found that denervation does not impair digit tip regeneration. Histological analysis showed the amputation stump proceeds through the expected phases of wound healing, blastema formation, and tissue outgrowth, and that regenerate bone volume is not significantly impaired in denervated digits. Interestingly, despite minimal change in regenerative outcome, bulk RNA sequencing identified significant changes in gene expression over time during regeneration in the absence of innervation. This study is the first to use RNA sequencing to characterize changes in gene expression during digit tip regeneration in the absence of innervation. Overall we show that digit tip regeneration is not dependent on innervation and our results suggest that regeneration may be achieved through activation of redundant signalling pathways.