Human neural stem cells: region-specific properties and prospects for cell therapy

Sammanfattning: Cell replacement by neural transplantation can, in animal models of neurodegenerative diseases, reconstruct damaged brain circuitry. In the clinical situation, the graft material used for cell therapy must, most likely, be of human origin. The human fetal brain is one potential source of neural stem cells (NSCs) for cell replacement therapy in neurodegenerative disorders such as stroke. Stroke is the leading cause of disability in adult humans and treatments for beneficial and efficient recovery are today lacking. In the most common form of human stroke, i.e. occlusion of the middle cerebral artery, mainly neurons in the cortex and striatum die. Therefore, we wanted to generate NSCs lines derived from the human fetal cortex and striatum and explore whether they maintain an intrinsic cellular identity in culture, consistent with their region of origin. Moreover, we wanted to investigate their capacity and potential after transplantation into the striatum of intact newborn and stroke-lesioned adult rats. Furthermore, we wanted to determine whether we could drive the NSCs towards neuronal fate by overexpressing the transcription factor Pax6. We found that the cortical and striatal NSCs have similar properties during expansion as neuropsheres. However, upon long-term differentiation in vitro, the cortical and striatal NSCs generated region-specific neuronal subtypes. After transplantation into the neonatal rat striatum, both cortical and striatal NSCs survived well and migrated similar distances, and had the capacity to differentiate into astrocytes, oligodendrocytes and mature neurons. When the NSCs were grafted into the striatum of rats subjected to stroke, both cortical and striatal NSCs survived and migrated to the same extent, and almost exclusively generated neurons outside the graft core. However, the striatal NSCs occupied a larger volume of the striatum and generated a higher proportion of neurons with molecular identity of striatal neurons. Upon overexpression of Pax6, the in vitro generation of neurons increased from the striatal NSCs and with maintained region-specificity. When striatal NSCs overexpressing Pax6 was implanted into the neonatal rat, there was an increased generation of neuroblasts compared to control. Taken together, it is possible to consider cortical and striatal NSCs derived from the human fetus as a safe cell source with a very strong neurogenic capacity as promising candidates for cell replacement therapy. However, before any clinical application of cell replacement therapy can be considered, there are several key points to address; the selection of established and guaranteed safe cell sources with fully controllable differentiation potential, the complete knowledge of disease mechanisms and progression, the optimized number of cells and time for transplantation, and the careful selection of patients with best prognosis to benefit from cell therapy.