Cell Stem Cell 14, 228–236 (2014)

Fibroblasts can undergo reprogramming into different cell types through the introduction of genetic factors or small molecules, but creating functional β cells, which would find utility in treating Type I diabetes (T1D), has remained challenging. Li et al. found that they could generate mature pancreatic-like cells from fibroblasts through four distinct stages using transcription factors and growth factors. However, the efficiency of producing insulin-expressing cells was low. To increase this efficiency, the authors strove to identify small molecules from a known drug collection that could enhance production of these cell types at each stage. The addition of known epigenetic modifiers Bix-01294 and pVc to fibroblasts at an early stage increased the number of definitive endoderm progenitors, whereas the combination of four small molecules—retinoic acid, pVc, an inhibitor of TGF-β signaling (A83-01) and an inhibitor of Hedgehog signaling (LDE225)—could substitute for the use of growth factors in generating pancreatic precursors. Finally, the addition of SB203580 (an inhibitor of p38-MAPK signaling) and pVc at later stages increased the production of pancreatic-like cells. To verify that these pancreatic-like cells were functional, the authors transplanted these cells near the kidney capsule in a T1D mouse model and could detect rescue of blood glucose levels. Thus, the generation of functional β cells from fibroblasts could be a useful approach to treat both T1D and T2D.