Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration

Abstract

The corticospinal tract (CST) is the most important motor system in humans, yet robust regeneration of this projection after spinal cord injury (SCI) has not been accomplished. In rodent models of SCI, we report robust corticospinal axon regeneration, functional synapse formation and improved skilled forelimb function after grafting multipotent neural progenitor cells into sites of spinal cord injury. Corticospinal regeneration requires that grafts are driven toward caudalized (spinal cord), rather than rostralized, fates. Fully mature caudalized neural grafts also support corticospinal regeneration. Moreover, corticospinal axons can emerge from neural grafts and regenerate beyond the lesion, potentially related to attenuation of the glial scar. Rodent corticospinal axons also regenerate into human donor grafts of caudal spinal cord identity. Collectively, these findings indicate that spinal cord “replacement” with homologous neural stem cells enables robust regeneration of the corticospinal projection within and beyond spinal cord lesion sites, achieving a major unmet goal of spinal cord injury research and opening new possibilities for translation.

Direct interaction of receptor tyrosine kinases, EphA4 and PDGFRβ, plays an important role in the proliferation of neural stem cells

“…37 Neural stem cells derived from H9 human embryonic stem cells (H9-NSCs) were obtained from Thermo Fisher Scientific (Waltham, MA, USA) and cultured following the manufacturer's protocols. 38 Cells were passaged to generation 3 for RNA extraction, cell proliferation assay, or immunoprecipitation and immunoblotting.…”

Prolonged human neural stem cell maturation supports recovery in injured rodent CNS

“…Neural stem cells (NSCs) differentiate into neurons and glia and can potentially replace lost neural systems after central nervous system (CNS) injury (1)(2)(3)(4)(5)(6)(7)(8). When implanted into sites of spinal cord injury (SCI), rat-and human-derived multipotent neural progenitor cells, human embryonic stem cell-derived (ESC-derived) NSCs, and human induced pluripotent stem cell-derived (iPSC-derived) NSCs all extend very large numbers of axons over long distances and form synapses with host neurons (4,5) that in some cases support functional improvement (4,(8)(9)(10).…”

New Aspects of Graft-induced Central Plasticity and Neuroregeneration at T 10 in a Rat Model†

“…Until now, traumatic paraplegia by severance of the spinal cord (SC) remains an irreversible condition. Basically, current clinical treatment strategies are targeted to promote axon regeneration and outgrowth beyond the scar formation following SC avulsion [1][2][3][4][5][8][9][10][11][12][13][14][15][16][17][18][20][21][24][25][26][27][28][29][30][31][72][73][74][75][76][77][78][79][80][81][82][83][84][85] Previous experimental and clinical studies together with GB have aroused some hope that paraplegic patients might achieve some selective voluntary muscle reinnervation after grafting the first motor neuron to skeletal hip muscles [10,11,25,72,73].…”

“…Filli and coworkers suggest [74] that "severed reticulo-spinal fibers, which are part of the phylogenetically oldest motor command system, spontaneously arborize and form contacts onto a plastic propriospinal relay, thereby bypassing the lesion" quote end. These rearrangements were accompanied by substantial locomotor recovery, implying a potential physiological relevance of the detour in restoration of motor function after spinal injury" [75]. The distal segment of a transected nerve is known to undergo Wallerian degeneration and can subsequently regenerate by growth of the proximal axon segment [76].…”