Therapeutic Application of Neural Stem Cells for Neonatal Hypoxic-ischemic Brain Injury

Neural stem cells (NSCs) are characterized by a capacity for self-renewal, differentiation into multiple neural cell lineages, and migration toward damaged sites in the central nervous system (CNS). NSCs expanded in culture could be implanted into the brain where they integrate into host neural circuitry and stably express foreign genes. It hence appears that transplantation of NSCs has been proposed as a promising therapeutic strategy in neurological disorders. During hypoxic-ischemic (HI) brain injury, factors are transiently elaborated to which NSCs respond by migrating to degenerating regions and differentiating towards replacement of dying neural cells. In addition, NSCs serve as vehicles for gene delivery and appear capable of simultaneous neural cell replacement and gene therapy (e.g. with factors that might enhance neuronal differentiation, neurites outgrowth, proper connectivity, neuroprotection, and/or immunomodulatory substances). When combined with certain synthetic biomaterials, NSCs may be even more effective in 'engineering' the damaged CNS towards reconstitution. Human NSCs were isolated from the forebrain of an aborted fetus at 13 weeks of gestation and were grown as neurospheres in cultures. After the characterization of human NSCs in preclinical testing and the approval of the IRB, a clinical trial of the transplantation of human NSCs into patients with severe perinatal HI brain injury has been performed. The existing data from these clinical trials have shown to be safe, well tolerated, and of neurologically-some benefits. Therefore, long-term and large scale multicenter clinical study is required to determine its precise therapeutic effect and safety.

Amyloid-beta oligomers regulate the properties of human neural stem cells through GSK-3beta signaling

Alzheimer's disease (AD) is the most common cause of age-related dementia. The neuropathological hallmarks of AD include extracellular deposition of amyloid-beta peptides and neurofibrillary tangles that lead to intracellular hyperphosphorylated tau in the brain. Soluble amyloid-beta oligomers are the primary pathogenic factor leading to cognitive impairment in AD. Neural stem cells (NSCs) are able to self-renew and give rise to multiple neural cell lineages in both developing and adult central nervous systems. To explore the relationship between AD-related pathology and the behaviors of NSCs that enable neuroregeneration, a number of studies have used animal and in vitro models to investigate the role of amyloid-beta on NSCs derived from various brain regions at different developmental stages. However, the Abeta effects on NSCs remain poorly understood because of conflicting results. To investigate the effects of amyloid-beta oligomers on human NSCs, we established amyloid precursor protein Swedish mutant-expressing cells and identified cell-derived amyloid-beta oligomers in the culture media. Human NSCs were isolated from an aborted fetal telencephalon at 13 weeks of gestation and expanded in culture as neurospheres. Human NSCs exposure to cell-derived amyloid-beta oligomers decreased dividing potential resulting from senescence through telomere attrition, impaired neurogenesis and promoted gliogenesis, and attenuated mobility. These amyloid-beta oligomers modulated the proliferation, differentiation and migration patterns of human NSCs via a glycogen synthase kinase-3beta-mediated signaling pathway. These findings contribute to the development of human NSC-based therapy for AD by elucidating the effects of Abeta oligomers on human NSCs.

Growth factor-expressing human neural progenitor cell grafts protect motor neurons but do not ameliorate motor performance and survival in ALS mice

Neural progenitor cells (NPs) have shown several promising benefits for the treatment of neurological disorders. To evaluate the therapeutic potential of human neural progenitor cells (hNPs) in amyotrophic lateral sclerosis (ALS), we transplanted hNPs or growth factor (GF)-expressing hNPs into the central nervous system (CNS) of mutant Cu/Zn superoxide dismutase (SOD(1G93A)) transgenic mice. The hNPs were engineered to express brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), VEGF, neurotrophin-3 (NT-3), or glial cell-derived neurotrophic factor (GDNF), respectively, by adenoviral vector and GDNF by lentiviral vector before transplantation. Donor-derived cells engrafted and migrated into the spinal cord or brain of ALS mice and differentiated into neurons, oligodendrocytes, or glutamate transporter-1 (GLT1)-expressing astrocytes while some cells retained immature markers. Transplantation of GDNF- or IGF-1-expressing hNPs attenuated the loss of motor neurons and induced trophic changes in motor neurons of the spinal cord. However, improvement in motor performance and extension of lifespan were not observed in all hNP transplantation groups compared to vehicle-injected controls. Moreover, the lifespan of GDNF-expressing hNP recipient mice by lentiviral vector was shortened compared to controls, which was largely due to the decreased survival times of female animals. These results imply that although implanted hNPs differentiate into GLT1-expressing astrocytes and secrete GFs, which maintain dying motor neurons, inadequate trophic support could be harmful and there is sexual dimorphism in response to GDNF delivery in ALS mice. Therefore, additional therapeutic approaches may be required for full functional recovery.

Gene and Cell Replacement via Neural Stem Cells

Neural stem cells (NSCs) are operationally defined by their ability to self-renew, to differentiate into cells of all glial and neuronal lineages throughout the neuraxis, and to populate developing or degenerating central nervous system (CNS) regions. Thus their use as graft material can be considered analogous to hematopoietic stem cell-mediated reconstitution and gene transfer. The recognition that NSCs propagated in culture could be reimplanted into mammalian brain, where they might integrate appropriately throughout the mammalian CNS and stably express foreign genes, has unveiled a new role for neural transplantation and gene therapy and a possible strategy for addressing the CNS manifestations of diseases that heretofore had been refractory to intervention. NSCs additionally have the appealing ability to home in on pathology, even over great distances. Such observations help to advance the idea that NSCs - as a prototype for stem cells from other solid organs - might aid in reconstructing the molecular and cellular milieu of maldeveloped or damaged CNS.