Neural stem cell therapy: A case of identity

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Science Translational Medicine  06 Jun 2018:
Vol. 10, Issue 444, eaau0464
DOI: 10.1126/scitranslmed.aau0464


Human pluripotent stem cell–derived neurons with visual cortex identity show circuit-specific integration into lesioned mouse visual cortex but not lesioned motor cortex.

Neuronal loss is a hallmark of many neurological disorders, from degenerative disorders such as Alzheimer’s and Parkinson’s diseases to stroke. The possibility of restoring function by transplantation of cells to replace those lost is highly appealing but fraught with technical difficulty. However, gradual progress toward this goal continues to be made. Key to success in restoring connectivity, and hence functional recovery, is the functional integration of the transplanted cells in their new environment, including the formation of working connections in a manner appropriate to the affected brain region.

In this study, Espuny-Camacho et al. use human pluripotent embryonic stem cells to generate neuronal precursors committed to a visual cortex fate. They generated cortical lesions in adult mice by injection of a neurotoxin, ibotenic acid, in either the visual cortex or motor cortex and then transplanted the human stem cell–derived neurons into the lesioned area. In both regions, grafted neurons could be seen many months later in over half of transplants, a promising finding in itself. Careful, brain-wide analysis of the location and projections of these cells revealed that in visual cortex lesions, the transplanted cells matured and sent out long-range axonal projections across the brain, specifically to known targets of the visual cortex. However, when grafted into motor cortex lesions, the cells not only showed delayed maturation but also much lower levels of long-range target innervation. Interestingly, when they did project to distant brain regions, they were predominantly found in visual cortex targets, suggesting that their cellular identity may dictate this critical behavior. Overall, this study indicates that successful integration of human stem cell–derived neurons depends on matching their cellular “area” identity to the target region.

These findings are important as the authors have replicated their previous findings using mouse embryonic stem cell neuronal precursors with human cells. However, the necessity of matching area identity remains controversial. It may be that grafting more immature cells could circumvent this requirement, although the use of immature precursors in turn could open a greater potential for off-target or detrimental effects. Either way, we are a step further toward understanding how to persuade transplanted human cells to accurately recapitulate neuronal connectivity in the context of neuronal loss.

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