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Deciphering the Molecular Mechanisms Controlling Spinal Cord Regeneration

Review of “Injured adult neurons regress to an embryonic transcriptional growth state” from Nature by Stuart P. Atkinson

The transplantation of spinal-cord-derived neural progenitor cells (NPCs) into sites of spinal cord injury can promote the regeneration of corticospinal axons and the restoration of forelimb function [1, 2]; however, we lack a general understanding of the molecular mechanisms involved in this process. 

Now, researchers from the laboratories of Gunnar H. D. Poplawski and Mark H. Tuszynski (University of California San Diego, La Jolla, CA, USA) have profiled motor neurons of the mouse corticospinal tract to identify a ‘regenerative transcriptome’ after spinal cord injury and NPC grafting. In their new study, the team highlights a shift in the regenerating corticospinal motor neuron transcriptome towards an immature state following injury and establishes the overall importance of the huntingtin gene as a central hub for the regenerative transcriptome [3].

Initial transcriptional analyses by the authors established an identical transcriptomic profile in regenerating corticospinal motor neurons after injury alone (dorsal column lesions at cervical spinal cord level 5) and after the administration of NPCs to induce corticospinal regeneration. While the transcriptomic alterations endured for around two weeks in the untreated injured mice, NPC administration sustained the injury-associated differential gene expression profile over time and did not initiate an alternative growth program. 

Detailed analysis of transcriptional alterations, which included genes related to stem cells and proliferation-, differentiation-, and cell cycle progression-related functions, highlighted a reversion of regenerating adult neurons to a transcriptional state with similarities to embryonic host corticospinal motor neurons. Interestingly, this analysis also established the huntingtin gene as a central hub in the regenerative transcriptome; in confirmation, the deletion of huntingtin significantly reduced corticospinal sprouting and regeneration after injury, thereby establishing huntingtin as a critical mediator of neural plasticity. 

Overall, the insights gleaned from this fascinating study may aid the development of new and improved strategies aimed at inducing the repair/regeneration of corticospinal axons and restoring forelimb function after spinal cord injury [1].

For more on the molecular mechanisms controlling neural regeneration following NPC transplantation into the injured spinal cord, stay tuned to the Stem Cells Portal!

References

  1. Kadoya K, Lu P, Nguyen K, et al., Spinal Cord Reconstitution with Homologous Neural Grafts Enables Robust Corticospinal Regeneration. Nature Medicine 2016;22:479-487.
  2. Coumans JV, Lin TT-S, Dai HN, et al., Axonal Regeneration and Functional Recovery after Complete Spinal Cord Transection in Rats by Delayed Treatment with Transplants and Neurotrophins. The Journal of Neuroscience 2001;21:9334.
  3. Poplawski GHD, Kawaguchi R, Van Niekerk E, et al., Injured Adult Neurons Regress to an Embryonic Transcriptional Growth State. Nature 2020;581:77-82.