Human neural stem cell differentiation following transplantation into spinal cord injured mice: association with recovery of locomotor function.
Stem cells are under intense investigation as potential therapeutics for central nervous system (CNS) injury and disease. However, several reports have suggested that stem cells grown as neurospheres and transplanted into an injured environment preferentially differentiate into astrocytes, contributing to glial scar. Further, the relationship between functional recovery and cell transplantation has not been empirically investigated in early studies. Using severe combined immunodeficient (scid) mice to minimize xenograft rejection, we report that prospectively isolated human fetal CNS-derived stem cells grown as neurospheres (hCNS-SCns) survive, migrate and express differentiation markers for neurons and oligodendrocytes after long-term engraftment in spinal cord injured (SCI) NOD-scid mice. Only rarely do these cells differentiate into glial fibrillary acidic protein (GFAP)-positive astrocytes, with no apparent contribution to glial scar. hCNS-SCns engraftment was associated with recovery of locomotor function. After long-term engraftment and stable behavioral plateaus in recovery were achieved (4 months post-transplantation), locomotor improvements were abolished by selective ablation of human cells with diphtheria toxin (DT). These data suggest that hCNS-SCns survival is required for locomotor recovery, possibly via differentiation and integration of human cells in the mouse host or continuous supply of trophic or other support necessary for gains in host cell function.
Cummings
Brian J
BJ
Department of Physical Medicine and Rehabilitation, University of California, Irvine, CA 92697, USA. cummings@uci.edu
Uchida
Nobuko
N
Tamaki
Stan J
SJ
Anderson
Aileen J
AJ
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D046529:Microscopy, Electron, Transmission; D009043:Motor Activity / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000637:transplantation*; D009836:Oligodendroglia / Q000166:cytology; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000473:pathology / Q000601:surgery*; D033581:Stem Cell Transplantation