Abstract
The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter.
Highlights
Ever since the discovery of naturally occurring neural stem cells (NSCs) residing in discrete niches of the adult mammalian central nervous system (CNS) [1,2,3,4,5], these cryptic cell populations received considerable interest in terms of their contribution to brain plasticity, learning, and repair
This study focused on BDNF expression-mediated effects of NSCs on the extent of injury and subsequent functional improvements, a proper description of all three cell types was not provided
In light of the observations from this study it will be of interest to see whether in mouse injury models with distinct focal brain region impairment NSC transplantation into the neonatal developing brain would result into more widespread cell integration as opposed to the generally observed focal NSC occurrence around adult lesion sites
Summary
Ever since the discovery of naturally occurring neural stem cells (NSCs) residing in discrete niches of the adult mammalian central nervous system (CNS) [1,2,3,4,5], these cryptic cell populations received considerable interest in terms of their contribution to brain plasticity, learning, and repair. While the large degree of heterogeneity of applied NSCs, even when isolated from defined stem cell niches [8,9], is likely to affect reproducibility, standardization, and clinical translation, different brain regions and injury types contribute to the number of parameters affecting cell fate acquisition. It would be important to define rate limiting and dominating parameters to ensure a larger degree of comparability across different investigations and to promote the development of protocols that will eventually lead to a successful clinical translation
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