Prospects for engineering neurons from local neocortical cell populations as cell-mediated therapy for neurological disorders

Abstract

There is little cell replacement following neurological injury, limiting the regenerative response of the CNS. Progress in understanding the biology of neural stem cells has raised interest in using stem cells for replacing neurons lost to injury or to disease. Stem cell therapy may also have a role in rebuilding deficient neural circuitry underlying mood disorders, epilepsy, and pain modulation among other roles. In vitro expansion of stem cells with directed differentiation prior to transplantation is one approach to stem cell therapy. Emerging evidence suggests that it may be possible to convert in vivo endogenous neural cells to a neuronal fate directly, providing an alternative strategy for stem cell therapy to the CNS. This review assesses the evidence for engineering a subtype-specific neuronal fate of endogenous neural cells in the cerebral cortex as a function of initial cell lineage, reactive response to injury, conversion factors, and environmental context. We conclude with a discussion of some of the challenges that must be overcome to move this alternative in vivo engineered conversion process toward becoming a viable therapeutic option.

Keywords: direct in vivo conversion; endogenous recruitment; injury-induced neurogenesis; neural stem cell; neuronal replacement; reprogramming.

Figure 1. Calibrated comparison of brain size from mouse to human

(A) Coronal cross sections through mouse, rat, rhesus monkey, and human illustrate their significant scaling differences and underscores the differences in migratory distance that SVZ-derived neural progenitors would be required to travel to replace lost cortical cells between animal models and human subjects. (B) The relative ratio of white matter to gray matter is very low in the mouse brain, whereas the abundance of white matter is greater than grey matter in the human brain (Panel A). The expansion of white matter in the human brain is primarily responsible for the increased challenge of migratory replacement for human subjects. Images of rhesus and human brain are from the MSU Brain Biodiversity Bank (https://www.msu.edu/~brains/copyright.html; National Science Foundation) and images for mouse and rat brain are from Brain Maps.org (Mikula et al., 2007).