Isolating endoderm and understanding developmental signals: defining sequential steps of embryonic stem cell differentiation to β cells

False starts have marked early work towards efficiently differentiating embryonic stem cells to β cells. Recent research has returned to foundations of developmental biology by focusing first on achieving definitive endoderm differentiation as a requisite step to ultimately producing high-quality islet endocrine cells. The present review will highlight recent demonstrations of definitive endoderm differentiation from embryonic stem cells and emphasize how mesenchymal signals, learned from embryological studies, may be used to further induce pancreatic specification from embryonic stem cells. Recently, advances have been made in the identification and purification of cells having the expected characteristics of definitive endoderm, from which all pancreatic cell types are derived. These studies have defined putative markers of definitive endoderm and provided insights into embryological signals controlling endoderm formation in mice and humans. Emerging data about the relationship between developing definitive endoderm and the surrounding mesenchyme now suggest possible methods of replicating the pancreatic developmental process in embryonic stem cells in vitro. Lessons learned from understanding developmental mechanisms of definitive endoderm formation and pancreas specification in lower organisms and adapted in application to human embryonic stem cells will drive further advances in this field.