[Show abstract][Hide abstract] ABSTRACT: Many diseases of the central nervous system (CNS), particularly those of genetic, metabolic, or infectious/inflammatory etiology, are characterized by "global" neural degeneration or dysfunction. Therapy might require widespread neural cell replacement, a challenge not regarded conventionally as amenable to neural transplantation. Mouse mutants characterized by CNS-wide white matter disease provide ideal models for testing the hypothesis that neural stem cell transplantation might compensate for defective neural cell types in neuropathologies requiring cell replacement throughout the brain. The oligodendrocytes of the dysmyelinated shiverer (shi) mouse are "globally" dysfunctional because they lack myelin basic protein (MBP) essential for effective myelination. Therapy, therefore, requires widespread replacement with MBP-expressing oligodendrocytes. Clonal neural stem cells transplanted at birth-using a simple intracerebroventricular implantation technique-resulted in widespread engraftment throughout the shi brain with repletion of MBP. Accordingly, of the many donor cells that differentiated into oligodendroglia-there appeared to be a shift in the fate of these multipotent cells toward an oligodendroglial fate-a subgroup myelinated up to 52% (mean = approximately 40%) of host neuronal processes with better compacted myelin of a thickness and periodicity more closely approximating normal. A number of recipient animals evinced decrement in their symptomatic tremor. Therefore, "global" neural cell replacement seems feasible for some CNS pathologies if cells with stem-like features are used.
Proceedings of the National Academy of Sciences 07/1999; 96(12):7029-34. DOI:10.1073/pnas.96.12.7029 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Stable clones of neural stem cells (NSCs) have been isolated from the human fetal telencephalon. These self-renewing clones give rise to all fundamental neural lineages in vitro. Following transplantation into germinal zones of the newborn mouse brain they participate in aspects of normal development, including migration along established migratory pathways to disseminated central nervous system regions, differentiation into multiple developmentally and regionally appropriate cell types, and nondisruptive interspersion with host progenitors and their progeny. These human NSCs can be genetically engineered and are capable of expressing foreign transgenes in vivo. Supporting their gene therapy potential, secretory products from NSCs can correct a prototypical genetic metabolic defect in neurons and glia in vitro. The human NSCs can also replace specific deficient neuronal populations. Cryopreservable human NSCs may be propagated by both epigenetic and genetic means that are comparably safe and effective. By analogy to rodent NSCs, these observations may allow the development of NSC transplantation for a range of disorders.
[Show abstract][Hide abstract] ABSTRACT: Dysfunctional myelination or oligodendroglial abnormalities play a prominent role in a vast array of pediatric neurological diseases of genetic, inflammatory, immunological, traumatic, ischemic, developmental, metabolic, and infectious causes. Recent advances in glial cell biology have suggested that effective remyelination strategies may, indeed, be feasible. Evidence for myelin repair is accumulating in various experimental models of dysmyelinating and demyelinating disease. Attempts at remyelination have either been directed towards creating myelin de novo from exogenous sources of myelin-elaborating cells or promoting an intrinsic spontaneous remyelinating process. Ultimately, some disorders of myelin may require multiple repair strategies, not only the replacement of dysfunctional cells (oligodendroglia) but also the delivery or supplementation of gene products (ie, growth factors, immune modulators, metabolic enzymes). Although primary oligodendrocytes or oligodendroglial precursors may be effective for glial cell replacement in certain discrete regions and circumstances and although various genetic vectors may be effective for the delivery of therapeutic molecules, multipotent neural stem cells may be most ideally suited for both gene transfer and cell replacement on transplantation into multiple regions of the central nervous system under a wide range of pathological conditions. We propose that, by virtue of their inherent biological properties, neural stem cells possess the multifaceted therapeutic capabilities that many diseases characterized by myelin dysfunction in the pediatric population may demand.