Neural progenitor cell grafts promote corticospinal nerve regeneration in spinal cord injury [PreClinical]

1. When neural progenitor cells (NPCs) derived from rat embryos were injected into the site of spinal cord injury (SCI) in rats, extensive regeneration of corticospinal axons into the graft and improved functional motor recovery were observed.

2. In rats, reinnervation of graft sites with corticospinal axons was also achieved using NPCs derived from a human embryo and NPCs derived from human induced pluripotent stem cells (iPSCs).

Evidence Rating Level: 3 (Average)       

Study Rundown: SCI is a devastating condition affecting millions of people worldwide, and can result in loss of sensation and function in the limbs or other regions of the body. SCI can affect the corticospinal tract (CST), a bundle of nerve fibers descending from the cerebral cortex through the spinal cord which is critically involved in motor function. Corticospinal regeneration following SCI has been met with limited success, in part because scarring at the lesion site opposes reinnervation.

In this study, multipotent NPCs taken from rat embryos were transplanted into rats two weeks after SCI. Six weeks later, CST axons were observed to populate the graft site. When SCI involved smaller lesions, CST axons extended beyond the caudal graft-host border, indicative of reinnervation of the lesion site. Rats given NPC grafts showed superior recovery of motor function, including grasping and reaching capabilities, in comparison to untreated animals with SCI. To further explore the potential clinical application of this work, the researchers transplanted multipotent NPCs derived from a human embryo into rats with SCI lesions and showed resulting corticospinal generation in the graft site. Grafts derived from human iPSCs which were promoted toward an NPC spinal cord-like fate showed similar results.

While the many types of animals and lesions tested in this work demonstrate the robustness of this approach, consistency in experimental setups will be important in elucidating the particular types of SCI where this therapy might be most useful. Nonetheless, this work suggests a new approach to corticospinal regeneration which may be effective in the clinical setting.

Click to read the study in Nature Medicine

Relevant Reading: Review of transplantation of neural stem/progenitor cells for spinal cord injury

In-Depth [animal study]: NPCs expressing green fluorescent protein were taken from embryonic day-14 rat spinal cord primordia. In six adult rats, complete transection at the T3 vertebral body was followed two weeks later with a graft of 10 µL NPCs. CST axons were labeled by injecting animals with biotinylated dextran amine (BDA), and extended as far as 3 mm toward the caudal border of the graft-lesion site. In a second experiment, a 1.5 µL NPC volume was engrafted into smaller lesion sites. Four rats had resulting graft-lesions measuring ~1 mm, and all of these animals showed corticospinal axon regeneration extending beyond the caudal graft-host interface.

Experiments measuring recovery of motor function used bilateral CST lesions and right dorsal-quadrant spinal cord lesions. Rats given rat-derived NPC grafts two weeks following SCI showed superior performance on the staircase test, which involved reaching sugar pellets on successively lower stairs from a landing above. Compared to untreated animals, rats given NPCs ate significantly more pellets at time points beginning 5 weeks after grafts (p<0.05 , n=7 per group). The treated group also reached lower stairs and ate a greater percentage of initially displaced pellets (p<0.05 at select individual time points).

In experiments using human cells, NPCs isolated from a 9-week-old embryo were transplanted into rats given CST lesions at the C4 vertebral site. CST axons were observed to extend as far as 1.5 mm into the graft-lesion site. Similar regeneration distances were achieved when grafts used human iPSCs which were driven toward a spinal cord NPC fate.

Image: PD

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