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Prolonged human neural stem cell maturation supports recovery in injured rodent CNS
Paul Lu, … , Eileen Staufenberg, Mark H. Tuszynski
Paul Lu, … , Eileen Staufenberg, Mark H. Tuszynski
Published August 21, 2017
Citation Information: J Clin Invest. 2017;127(9):3287-3299. https://doi.org/10.1172/JCI92955.
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Research Article Neuroscience Article has an altmetric score of 80

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

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Abstract

Neural stem cells (NSCs) differentiate into both neurons and glia, and strategies using human NSCs have the potential to restore function following spinal cord injury (SCI). However, the time period of maturation for human NSCs in adult injured CNS is not well defined, posing fundamental questions about the design and implementation of NSC-based therapies. This work assessed human H9 NSCs that were implanted into sites of SCI in immunodeficient rats over a period of 1.5 years. Notably, grafts showed evidence of continued maturation over the entire assessment period. Markers of neuronal maturity were first expressed 3 months after grafting. However, neurogenesis, neuronal pruning, and neuronal enlargement continued over the next year, while total graft size remained stable over time. Axons emerged early from grafts in very high numbers, and half of these projections persisted by 1.5 years. Mature astrocyte markers first appeared after 6 months, while more mature oligodendrocyte markers were not present until 1 year after grafting. Astrocytes slowly migrated from grafts. Notably, functional recovery began more than 1 year after grafting. Thus, human NSCs retain an intrinsic human rate of maturation, despite implantation into the injured rodent spinal cord, yet they support delayed functional recovery, a finding of great importance in planning human clinical trials.

Authors

Paul Lu, Steven Ceto, Yaozhi Wang, Lori Graham, Di Wu, Hiromi Kumamaru, Eileen Staufenberg, Mark H. Tuszynski

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Figure 6

Host axonal regeneration and behavioral outcomes.

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Host axonal regeneration and behavioral outcomes.
(A and B) Host 5-HT–la...
(A and B) Host 5-HT–labeled serotonergic axons regenerated into GFP-expressing human NSC grafts in a C5 hemisection lesion site 1 and 18 months after grafting. Dashed lines indicate the host/graft (h/g) interface. (C) Higher-magnification image shows 5-HT–labeled host axons regenerating into a GFP-expressing human NSC graft. The 5-HT–labeled structures colocalized with Syn in a Z-stack image, 18 months after grafting. (D) 5-HT quantification reveals that host serotonergic penetration of grafts was stable over time (P = 0.7, by ANOVA), for 1 (n = 3), 3 (n = 3), 6 (n = 5), 12 (n = 3), and 18 months (n = 4). (E) Forepaw placement accuracy on a behavioral grid-walking task was measured monthly for the first 4 months and bimonthly thereafter. Following an initial period of modest recovery from 0 to 2 months after lesioning, functional performance thereafter was stable in both grafted (n = 7) and control lesion (n = 5) groups and did not improve from 1 to 12 months (P = 0.62, by 2-way repeated-measures ANOVA comparing graft and lesion-only groups from 1 to 12 months). The control group was perfused at a preplanned anatomical endpoint of 12 months. (F) Functional testing in NSC-grafted animals continuing beyond 12 months (n = 4) revealed a significant, 2.7-fold late recovery of function compared with their own stable functional baseline at 12 months. **P < 0.02 and *P < 0.05, by post-hoc Fisher’s exact test comparing performance at 18 months at the indicated time points. Scale bars: 58 μm (A and B); 8 μm (C).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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