Direct conversion of fibroblasts to functional neurons by defined factors
Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modelling and regenerative medicine. The discovery that differentiated cells such as fibroblasts can be reprogrammed to pluripotency, producing iPS (induced pluripotent stem) cells, has generated much interest because of their potential therapeutic uses. Now Vierbuchen et al. show that mature differentiated cells can be directed, using a cocktail of transcription factors distinct from those used for generating iPS cells, to form functional neurons in vitro, without having to revert the fibroblasts to an embryonic state. Just three factors, Ascl1, Brn2 (Pou3f2) and Myt1l, suffice to convert mouse embryonic and postnatal fibroblasts into functional neurons. Mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors.
Here, mature differentiated cells are directed, via a combination of a few transcription factors (distinct from those described for generating iPS cells), to form functional neurons in vitro, without having to revert the fibroblasts to an embryonic state. Nature 2010 https://dx.doi.org/10.1038/nature08797
Thomas Vierbuchen, Austin Ostermeier, Zhiping P. Pang, Yuko Kokubu, Thomas C. Südhof, Marius Wernig