July 2011

Creating fully functional neurons from non-neural somatic cells or pluripotential stem cells is one of the Holy Grails of developmental and regenerative neurobiology. The scientific team led by Südhof and Wernig recently made the remarkable discovery that forced expression of a combination of just three transcription factors, Brn2 (also known as Pou3f2), Ascl1 and Myt1l, could efficiently convert mouse fibroblasts into functional induced neuronal (iN) cells. In this article, they capitalized on their prior work to determine whether this same approach is applicable to human cells. In the first set of experiments, they showed that the same three transcription factors could generate functional neurons from human pluripotent stem cells as early as 6 days after transgene activation. When combined with the basic helix–loop–helix transcription factor NeuroD1, these factors also converted fetal and postnatal human fibroblasts into iN cells showing typical neuronal morphologies and expressing multiple neuronal markers. Amazingly, this was maintained even after downregulation of the exogenous transcription factors. The vast majority of human iN cells were able to generate action potentials and many matured to receive synaptic contacts when co-cultured with primary mouse cortical neurons. These data demonstrate that non-neural human somatic cells, as well as pluripotent stem cells, can be converted directly into neurons by lineage-determining transcription factors. More work is needed to determine how these neurons can be further differentiated into the multitude of subtypes found in the nervous system. Nonetheless, this latest finding constitutes a major leap forward in stem cell biology these methods will undoubtedly facilitate the generation of patient-specific human neurons for in vitro disease modeling or future applications in regenerative medicine (Nature (26 May 2011) doi:10.1038).