Acinar-ductal cell rearrangement drives pancreas branching morphogenesis in an IGF/PI3K-dependent manner

SUMMARY During organ formation, progenitor cells need to acquire the diversity of cell identities found in the organ as well as organize themselves into distinct structural units. How these processes are coordinated, and how tissue architecture(s) are preserved despite the dramatic cell rearrangements occurring in developing organs remain unclear. Here, we identified cellular rearrangements between acinar and ductal progenitors as a mechanism to drive branching morphogenesis in the pancreas while preserving the integrity of the acinar-ductal functional unit. Using ex vivo and in vivo mouse models, we found that pancreatic ductal cells form clefts by protruding and pulling on the acinar basement membrane, which lead to acini splitting. Newly formed acini remain connected to bifurcated branches generated by ductal cell rearrangement. IGF/PI3K pathway regulates this process by controlling ductal cell fluidity. If components of the pathway are genetically or chemically dysregulated, ductal cell fluidity prevents branching and affects pancreatic cell fates. Hence, our results explain how acinar multiplication and branch bifurcation are synchronized during pancreas organogenesis.