One goal of regenerative medicine is to instructively convert adult cells into other cell types for tissue repair and regeneration. Although isolated examples of adult cell reprogramming are known, there is no general understanding of how to turn one cell type into another in a controlled manner. Here, using a strategy of re-expressing key developmental regulators in vivo, we identify a specific combination of three transcription factors (Ngn3 (also known as Neurog3) Pdx1 and Mafa) that reprograms differentiated pancreatic exocrine cells in adult mice into cells that closely resemble beta-cells. The induced beta-cells are indistinguishable from endogenous islet beta-cells in size, shape and ultrastructure. They express genes essential for beta-cell function and can ameliorate hyperglycaemia by remodelling local vasculature and secreting insulin. This study provides an example of cellular reprogramming using defined factors in an adult organ and suggests a general paradigm for directing cell reprogramming without reversion to a pluripotent stem cell state.

OLIG1 and OLIG2 are basic-helix-loop-helix (bHLH) transcription factors expressed in the pMN domain of the spinal cord, which sequentially generates motoneurons and oligodendrocytes. In Olig1/2 double-mutant mice, motoneurons are largely eliminated, and oligodendrocyte differentiation is abolished. Lineage tracing data suggest that Olig1(-/-)2(-/-) pMN progenitors instead generate V2 interneurons and then astrocytes. This apparent conversion likely reflects independent roles for OLIG1/2 in specifying motoneuron and oligodendrocyte fates. Olig genes therefore couple neuronal and glial subtype specification, unlike proneural bHLH factors that control the neuron versus glia decision. Our results suggest that in the spinal cord, Olig and proneural genes comprise a combinatorial code for the specification of neurons, astrocytes, and oligodendrocytes, the three fundamental cell types of the central nervous system.

Basic helix-loop-helix (bHLH) transcription factors have been identified for neurons and their precursors but not for glial cells. We have identified two bHLH factors, Oligo1 and Oligo2, that are specifically expressed in zones of neuroepithelium from which oligodendrocyte precursors emerge, as well as in the precursors themselves. Expression of Oligo2 in the spinal cord precedes that of platelet-derived growth factor receptor alpha (PDGFRalpha), the earliest known marker of oligodendrocyte precursors, by several days. Ectopic expression of Oligo2 in vivo causes ectopic expression of Sox10, an HMG-box transcription factor expressed in oligodendrocyte and other glial precursors. These data identify Oligo genes as the earliest known markers of oligodendrocyte lineage determination and suggest they play a causal role in this process.