A cross-species approach to uncover mechanisms of spinal cord regeneration

The ability to regenerate the injured spinal cord varies greatly among species, ranging from full regeneration in axolotls, to partial regeneration in spiny mice (Acomys), to very poor or no regeneration in mice and humans. However, the cellular and molecular mechanisms for these differences in regenerative capacity are poorly understood. Ependymal cells are the adult spinal cord stem cells, and key players in the spinal cord response to injury across species. I discovered that axolotl ependymal cells reactivate a developmental-like gene expression programme that orchestrates cell proliferation and cell fate decisions to successfully rebuild the spinal cord. I will now determine mechanistically why mouse ependymal cells have much more limited cell output and potency. My recent single-cell analysis identified ongoing ependymal cell maturation as a potential roadblock to spinal cord regeneration in mice. By working across species (axolotl, mice and Acomys), I will now directly compare successful, partial, and failed regeneration to discover the critical signalling pathways/factors and gene regulatory networks that account for differences in spinal cord regeneration capacity. This research will reveal both fundamental principles of spinal cord regeneration and the specific molecular mechanisms that limit and support it.