Cell fate is determined through a coordinated activity of transcription factors (TFs) and chromatin-remodeling complexes that establish a chromatin landscape that defines the gene products necessary for the specific function of that cell. Except rare instances of physiological transdifferentiation during development, such as the conversion of an intestinal epithelial cell into a neuron in C. elegans [1], cell fates remain stable and resist perturbations. However, forced expression of certain TFs can overcome the cells' barriers and impose a different fate. One of the first prominent demonstrations of an induced cell lineage change following forced expression of a TF was that the myogenic basic helix loop helix (bHLH) TF MyoD1 was able to convert fibroblasts into contracting muscle cells 2, 3. In a landmark discovery, Takahashi and Yamanaka succeeded in reprogramming fibroblasts back into cells of a pluripotent state, termed induced pluripotent stem (iPS) cells [4]. Up to that point, TFs were identified to induce specific cell types from closely related cells, such as B lymphocytes from macrophages or endocrine from exocrine pancreatic cells [5]. Our group first demonstrated that cell types can be directly converted into distantly related cell types, such as cells representing a different germ layer, by the discovery that the three TFs Ascl1, Brn2, and Myt1l, can convert fibroblasts directly into neurons [6]. The resulting neuronal-like cells formed synapses and fired action potentials, and we thus called them induced neuronal (iN) cells. While initial experiments were performed in mouse fibroblasts, with one additional factor, NeuroD1, it was also possible to convert human fibroblasts directly into iN cells [7]. Others identified additional TF combinations and microRNAs to convert human fibroblasts into neurons with various efficiencies 8, 9, 10. Most of the originally obtained iN cells were excitatory cells, but the work has inspired the development of methods for TF-driven direct reprogramming of various cells to obtain defined neuronal subtypes. In this way, dopamine, serotoninergic, cholinergic motor, and inhibitory Gamma-Aminobutyric Acid(GABA)ergic neurons have been generated 11, 12.

While direct reprogramming of fibroblasts to iN cells is not as scalable as other methods, such as reprogramming to iPS cells and subsequent differentiation, it has advantages, particularly in modeling age-related diseases [13]. Importantly, though, similar types of TFs can induce neuronal identity in various donor cell types, including liver, blood, and even pluripotent stem cells — iPS and embryonic stem (ES) cells 14, 15, 16. Since its initial discovery, TF-mediated direct conversion has become a popular way to generate defined somatic cell lineages from pluripotent stem cells. Figure 1.