Matters Arising: Insufficient Evidence That Pancreatic Β Cells Are Derived from Adult Ductal Neurog3-expressing Progenitors.

Understanding the origin of pancreatic 0 cells has profound implications for regenerative therapies in dia-betes. For over a century, it was widely held that adult pancreatic duct cells act as endocrine progenitors, but lineage-tracing experiments challenged this dogma. Gribben et al. recently used two existing lineage -tracing models and single-cell RNA sequencing to conclude that adult pancreatic ducts contain endocrine progenitors that differentiate to insulin-expressing 0 cells at a physiologically important rate. We now offer an alternative interpretation of these experiments. Our data indicate that the two Cre lines that were used directly label adult islet somatostatin-producing 0 cells, which precludes their use to assess whether 0 cells originate from duct cells. Furthermore, many labeled 0 cells, which have an elongated neuron-like shape, were likely misclassified as 0 cells because insulin-somatostatin coimmunolocalizations were not used. We conclude that most evidence so far indicates that endocrine and exocrine lineage borders are rarely crossed in the adult pancreas.