Human neuroepithelial stem cell regional specificity enables spinal cord repair through a relay circuit

Abstract

Traumatic spinal cord injury results in persistent disability due to disconnection of surviving neural elements. Neural stem cell transplantation has been proposed as a therapeutic option, but optimal cell type and mechanistic aspects remain poorly defined. Here, we describe robust engraftment into lesioned immunodeficient mice of human neuroepithelial stem cells derived from the developing spinal cord and maintained in self-renewing adherent conditions for long periods. Extensive elongation of both graft and host axons occurs. Improved functional recovery after transplantation depends on neural relay function through the grafted neurons, requires the matching of neural identity to the anatomical site of injury, and is accompanied by expression of specific marker proteins. Thus, human neuroepithelial stem cells may provide an anatomically specific relay function for spinal cord injury recovery.

Restoration of Direct Corticospinal Communication Across Sites of Spinal Injury

“…There is now substantial evidence that new relay circuits do form in grafts, based on the growth and synaptogenesis by host neurons into grafts and exuberant extension of graft-derived axons into distal host Compared to control animals that received EBFP and no NPCs, animals treated with AAV2-Retro-KLF6 and NPC grafts displayed significant improvements in forelimb placement on the horizontal ladder task, and in the ability to retrieve pellets on tissue (7,8). Moreover, recent findings indicate that these relay circuits contribute functionally to improvements in hindlimb stepping motions (9). There may be limits, however, to the ability of these relay circuits to restore motor control, particularly for fine forelimb movements normally controlled by the CST.…”

“…Again, this initial disorganization complicates any engagement of Hebbian processes to sculpt effective movement (41,42). It is notable that despite the robust growth in and out of NPC grafts and the existence of new relay connections, improvements even in stereotyped motions such as locomotion remain only partial (7,9).…”

“…In cases of incomplete injury, severed axons often sprout spontaneously to form new connections with spared tracts, creating detour circuits that re-route information around the injury (1)(2)(3)(4)(5)(6). Recent work involving transplants of neural progenitor cells has also succeeded in creating novel relay circuits as host axons invade and innervate graft-derived neurons, which in turn extend lengthy axons that innervate neurons in the caudal spinal cord (7)(8)(9). These indirect circuits, both endogenous and graft-derived, have yielded some gains in motor function after injury (4,6,7,9,10).…”

“…Recent work involving transplants of neural progenitor cells has also succeeded in creating novel relay circuits as host axons invade and innervate graft-derived neurons, which in turn extend lengthy axons that innervate neurons in the caudal spinal cord (7)(8)(9). These indirect circuits, both endogenous and graft-derived, have yielded some gains in motor function after injury (4,6,7,9,10). Recovery remains partial, however, even as various pharmacological, rehabilitation, and stimulation strategies have attempted to enhance their functional output (4,6).…”

3D Printed Neural Regeneration Devices

“…For example, when cortical neural progenitor cells were transplanted into a spinal cord injury, they survived but failed to successfully integrate. However, when spinal neural progenitor cells were transplanted into a spinal cord injury, they not only survived but matured, extended axons over long distances both rostrally and caudally, and may even have formed functional relays through the lesion area . Further, vascular networks need to be incorporated into the scaffold to provide perfusion of nutrients and diffusible elements.…”