Linking the brain and the spinal cord
Ken Kadoya from the laboratory of Mark Tuszynski, at the University of California, San Diego was able to show that grafts of neural progenitor or stem cells enable the regeneration of the corticospinal tract (CST) and the formation of functional synapses.
The CST is the most important motor system in humans and its failure to regenerate is a major limiting factor in the advancement of regenerative therapies.
Can stem cells enable the regeneration of the corticospinal axons?
The team investigated whether cell engraftment can enable a successful regeneration of the corticospinal neurons.
In a previously published paper in Nature Medicine the scientists report on a successful regeneration of corticospinal axons under certain conditions.
Regeneration of the CST requires the contact between the graft and the injured CST. It only occurred when the injected neural progenitor or stem cells showed the specific characteristics of spinal neurons, a so called ‘caudal neural fate’. This requirement on the cell characteristics could be demonstrated for cells derived from embryonic cells as well as for cells derived from human induced pluripotent stem cells (iPS). Grafting progenitors displaying midbrain or forebrain characteristics did not support corticospinal regeneration.
IPSCs are of specific interest for a stem cell based therapeutic strategy as they can be generated from a patient’s own cells and could serve as source for cell grafts. The team generated human iPS cells which were differentiated into neural progenitor cells with a caudal neural fate. Six week after grafting these cells in a spinal cord injury model, corticospinal axons regenerated into this human iPS derived cell graft.
Stem cells promote regeneration and create a functional relay
It is important to understand that the injected cells stimulated the regrowth of the corticospinal tract by providing a permissive graft milieu and a contact of the CST axons and the graft.
The grafted neural progenitor cells transformed themselves into new neurons on which the corticospinal tract neurons were connecting. These new neurons, acting as a relay, then grew caudally and were even able to project all the way to the limbs. Further testing proved that these new connections were functional and that a signal could be transmitted from the corticospinal tract to the newly formed neurons.
Stem cell based strategies cells always prompt another issue, the safety of these cells. The team reports that no ectopic cell collections or cell migration could be observed when grafting into closed lesion cavities.
What will happen next?
This work indicates that grafting specific human neural stem cells can reconstitute a spinal cord milieu enabling CST regeneration. However the underlying precise molecular constituents of the grafts must still be identified and also practical issues related to clinical translation including the optimal cell type and the establishment of safe methods for cell grafting remain to be addressed.