Cellular mechanisms influencing corticospinal and sensory axonal regeneration into neural stem cell grafts after SCI

Injured corticospinal tract axons regenerate robustly into caudalized neural progenitor cell (NPC) grafts and form functional synaptic connections with graft-derived neurons. However, the developmental fate of grafted NPCs, and whether those differentiated graft-derived neural subtypes might influence the regeneration of host axonal projections, remain unexplored. We demonstrate that upon maturation, embryonic spinal cord NPCs grafted into the injured, adult spinal cord contain clusters of dorsal spinal cord sensory interneurons that are potent zones of exclusion for regenerating corticospinal axons, but receive dense innervation by host CGRP+ sensory axons, reflecting the normal topographical projection patterns of these axons into distinct spinal cord laminae. Notably, these sensory neuron clusters form curved, layered structures populated by neuronal subtypes normally present in superficial dorsal horn laminae I-III, revealing the endogenous self-assembly of spinal cord dorsal horn-like structures within dissociated NPC grafts. These findings reveal a previously unknown barrier to corticospinal axon regeneration into otherwise highly permissive neural grafts, and more generally that axons of adult central and peripheral neurons reinnervate topographically appropriate regions of newly-born neurons after spinal cord injury. Moreover, these findings demonstrate the ability of transplanted dissociated embryonic NPCs to recapitulate assembly of adult spinal cord cytoarchitecture following engraftment into the injured, adult CNS.

1Dept. of Neurosciences, UCSD, La Jolla, CA; 2Veterans Affairs Med. Ctr., San Diego, CA
J.N. Dulin: None. A.F. Adler: None. H. Kumamaru: None. M.H. Tuszynski: None.

LINKS: Session 522 – Regenerative Approaches: Spinal Cord Injury

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