Cell replacement therapies for nervous system regeneration

Abstract

The adult brain was thought to be a slowly decaying organ, a sophisticated but flawed machine condemned to inevitable decline. Today we know that the brain is more plastic than previously assumed, as most prominently demonstrated by the constitutive birth of new neurons that occurs in selected regions of the adult brain, even in humans. However, the overall modest capacity for endogenous repair of the central nervous system (CNS) has sparked interest in understanding the barriers to neuronal regeneration and in developing novel approaches to enable neuronal and circuit repair for therapeutic benefit in neurodegenerative disorders and traumatic injuries. Scientists recently assembled in Baeza, a picturesque town in the south of Spain, to discuss aspects of CNS regeneration. The picture that emerged shows how an integrated view of developmental and adult neurogenesis may inform the manipulation of neural progenitors, differentiated cells, and pluripotent stem cells for therapeutic benefit and foster new understanding of the inner limits of brain plasticity.

Figure 1

Schema representing an integrated view of developmental and adult neurogenesis. During embryonic neurogenesis of the cerebral cortex, radial glial cells (RC2+, GLAST+, and Pax6+) give rise to neuroblasts that migrate to the cortex and differentiate into excitatory cortical projection neurons. In the adult brain, two regions retain the capacity to constitutively generate neurons (highlighted in blue): the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus. In the SVZ, slowly dividing NSC can give rise to rapidly dividing immature precursors. These actively proliferate and generate immature neuroblasts, which migrate in chains along the rostral migratory stream to the olfactory bulb (OB), where they differentiate into interneurons. Similarly, SGZ NSC in the dentate gyrus undergo proliferation, generate rapid amplifying intermediate progenitors, which then differentiate into dentate granule cells. Postnatal astroglia (GFAP+) may be efficiently converted into functional neurons in vitro under specific culture conditions and the use of neurogenic transcription factors (TFs), possibly offering an alternative cell source to pluripotent stem cells.