Generation of hNSC lines from hESC: Effect of selective derivation and transplantation niche on cell fate decisions and recovery after SCI

Funding Type: 
Comprehensive Grant
Grant Number: 
RC1-00337
Investigator: 
ICOC Funds Committed: 
$0
Public Abstract: 
Human Embryonic Stem Cells (hESCs) have become major focus of research effort for Central Nervous System (CNS) disease and injury, however, much research is needed to select for and generate sub-populations of hES-derived cells with optimal therapeutic potential for clinical application. Critically, there is essentially no data addressing whether different human stem cell populations have equivalent potential as cell-based therapeutics, an issue that will almost certainly depend on the type of disease or injury. While, for example, hESC-derived oligodendroglial committed progenitors have come quickly to the translational forefront, such lineage restricted progenitors are may not be optimal for CNS diseases/injuries in which neuronal loss and demyelination contribute variable components of the associated deficits, e.g. Spinal Cord Injury (SCI). By the same token, we know little about whether and how the environment into which therapeutic human stem cell populations would be transplanted will influence their ability to aid in recovery and repair. An additional for the clinical applicability of lineage restricted progenitors versus more flexible, multipotent, neural stem cell populations is migration. Neural restricted progenitors exhibit limited migration after transplantation, while glial restricted precursors are less constrained. The clinical consequences of such a limitation for repair/regeneration CNS injury and disease will therefore depend heavily upon transplantation site. Because some diseases, e.g. Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), would require a wide distribution of transplanted cells to serve a replacement function, limited migration will almost certainly be a hindrance to effective translation, especially when scaling up from rodent models to human reality. Similarly, surgical limitations on the ability to choose precisely appropriate transplantation sites in other instances, such as traumatic SCI, suggest greater efficacy may be obtained from cell populations with the potential to ‘search’ out and migrate towards the damaged niche. Understanding the mechanisms involved in these issues will increase the chances for successful design of clinical cell therapeutics and for successful translation of ESC research from bench to bedside. The proposed studies will therefore compare human Embryonic Stem Cell (hESC)-derived neural stem cell populations derived by three methods to test the hypothesis that positive selection for neural stem cells over lineage restricted progenitors will have beneficial consequences for survival, integration, and cell fate in the injured CNS niche. While multiple routes of NSC derivation may lead to beneficial effects, e.g. histological and/or locomotor recovery measures, we predict that different mechanisms will contribute to recovery depending on the cell population and heterogeneity.
Statement of Benefit to California: 
The RFA for the CIRM Comprehensive Research grants focuses on several key research areas judged to be of particular benefit for human Embryonic Stem Cell (hESC) research in California. The Specific Aims of this proposal addresses several of these in particular, including characterization and comparison of different hESC lines, understanding the regulation of cell fate decisions and influence of the injured CNS niche on these mechanisms, targeting lineage specific hESC differentiation, assessing hESC cell fate after transplantation, and assessing the tumorigenicity of transplanted hESC populations. Much research is needed to select for and generate sub-populations of hES-derived cells with optimal therapeutic potential for clinical application. Critically, there is essentially no data addressing whether different human stem cell populations have equivalent potential as cell-based therapeutics, an issue that will almost certainly depend on the type of disease or injury. While hESC-derived oligodendroglial committed progenitors have come quickly to the translational forefront, such lineage restricted progenitors are may not be optimal for CNS diseases/injuries in which neuronal loss and demyelination contribute variable components of the associated deficits, e.g. Spinal Cord Injury (SCI). By the same token, we know little about whether and how the environment into which therapeutic human stem cell populations would be transplanted will influence their ability to aid in recovery and repair. The proposed studies will therefore compare human Embryonic Stem Cell (hESC)-derived neural stem cell populations derived by three methods to test the hypothesis that positive selection for neural stem cells over lineage restricted progenitors will have beneficial consequences for survival, integration, and cell fate in the injured CNS niche. While multiple routes of NSC derivation may lead to beneficial effects, e.g. histological and/or locomotor recovery measures, we predict that different mechanisms will contribute to recovery depending on the cell population and heterogeneity.

© 2013 California Institute for Regenerative Medicine