In vivo reprogramming of adult pancreatic exocrine cells to β-cells

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 β-cells. The induced β-cells are indistinguishable from endogenous islet β-cells in size, shape and ultrastructure. They express genes essential for β-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. The prospects for diabetes treatment would be transformed if it became possible to turn an abundant supply of fully differentiated adult cells into insulin-secreting beta cells in a controlled manner. Although there are a few examples of producing beta-cells in such a way in the literature, the process has so far not been controllable. Hence the interest in this report, by Qiao Zhou et al. that mature exocrine pancreatic cells in live diabetic mice can be reprogrammed to become endocrine insulin-producing cells that closely resemble beta cells, passing from one differentiated state to another with no intermediate conversion to stem cells. The strategy is based on earlier studies of the transcription factors involved in pancreatic development: a cocktail of three factors (Ngn3, Pdx1 and Mafa) is the key ingredient. This paper shows that exocrine cells of the pancreas can be converted in vivo to insulin-secreting endocrine cells. Interestingly, the transdifferentiating cells did not have to revert to a more primitive, pluripotent state in this process, but seemed to move directly from one differentiated state to another.