Neural cells play an inhibitory role in pancreatic differentiation of pluripotent stem cells

Pancreatic endocrine β‐cells derived from embryonic stem (ES) cells and induced pluripotent stem (iPS) cells have received attention as screening systems for therapeutic drugs and as the basis for cell‐based therapies. Here, we used a 12‐day β‐cell differentiation protocol for mouse ES cells and obtained several hit compounds that promoted β‐cell differentiation. One of these compounds, mycophenolic acid (MPA), effectively promoted ES cell differentiation with a concomitant reduction of neuronal cells. The existence of neural cell‐derived inhibitory humoral factors for β‐cell differentiation was suggested using a co‐culture system. Based on gene array analysis, we focused on the Wnt/β‐catenin pathway and showed that the Wnt pathway inhibitor reversed MPA‐induced β‐cell differentiation. Wnt pathway activation promoted β‐cell differentiation also in human iPS cells. Our results showed that Wnt signaling activation positively regulates β‐cell differentiation, and represent a downstream target of the neural inhibitory factor.