Regrowing specific neurons back to their natural target regions allows mice to recover from paralysis, but random regrowth does not, according to a new study from a team of researchers from the University of California, Los Angeles (UCLA), the Swiss Federal Institute of Technology, and Harvard University. This work was published last week in Science. They used single-nucleus RNA sequencing to identify which neuronal subpopulations to target.
“Reestablishing the natural projections of characterized neurons forms an essential part of axon regeneration strategies aimed at restoring lost neurological functions,” they wrote.
In a 2018 study published in Nature, the team was able to trigger the regrowth of axons after spinal cord injury in rodents, but that did not lead to functional recovery. They found that three factors are essential for axon growth during development but are attenuated or lacking in adults—neuron intrinsic growth capacity, growth-supportive substrate,and chemoattraction.
They wrote that, “In combination, [these factors] are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents.”
In both mice and rats that providing these three mechanisms in combination, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls.
But this regrowth did not restore the rodents’ full mobility.
For the new study, the team aimed to determine whether directing the regeneration of axons from specific neuronal subpopulations to their original target regions could cure spinal cord injury in mice.
When the strategy was refined to include using chemical signals to attract and guide the regeneration of axons to their natural target region in the lumbar spinal cord, significant improvements in walking ability were observed in a mouse model of complete spinal cord injury.
“Our study provides crucial insights into the intricacies of axon regeneration and requirements for functional recovery after spinal cord injuries,” said Michael Sofroniew, MD, PhD, professor of neurobiology at the David Geffen School of Medicine at UCLA and a senior author of the new study. “It highlights the necessity of not only regenerating axons across lesions but also of actively guiding them to reach their natural target regions to achieve meaningful neurological restoration.”
The authors say understanding that re-establishing the projections of specific neuronal subpopulations to their natural target regions holds significant promise for the development of therapies aimed at restoring neurological functions in larger animals and humans.
However, the researchers also acknowledge the complexity of promoting regeneration over longer distances in non-rodents, necessitating strategies with intricate spatial and temporal features.
Still, they conclude that applying the principles laid out in their work “will unlock the framework to achieve meaningful repair of the injured spinal cord and may expedite repair after other forms of central nervous system injury and disease.”
