β-Cell Neogenesis From the Pancreatic Ductal Epithelium Revealed Dynamically by Long-term Intravital Imaging

Pancreatic β-cells can self-renew in the adult pancreas through replication, but the contribution of ductal progenitors to endocrine regeneration has been the subject of debate for two decades. While these mechanisms are not mutually exclusive, some lineage-tracing strategies suggest that intraductal endocrine cells cannot dynamically derive from ducts. Combining one such approach with a novel in vivo model in which live pancreatic slices are transplanted into the anterior chamber of the eye (ACE) of recipient mice, we show long-term growth of preexisting islets and real-time generation of neogenic insulin-expressing cells from ductal areas. Our results represent a departure from historical approaches to address these questions, which have been based on either static analyses of pancreatic tissue or "before and after" lineage-tracing designs. The slice-in-ACE model reveals the dynamic processes at play during regeneration and demonstrates the active formation of insulin-producing cells within the ductal network.

The adult pancreas' capacity to regenerate endocrine cells through ductal neogenesis has been disputed based on some pulse-chase lineage-tracing designs; however, no model described thus far has enabled the real-time study of regeneration in vivo. To facilitate long-term intravital imaging of pancreatic remodeling, we designed a novel system where pancreatic slices are transplanted into the anterior chamber of the eye of recipient mice. Using a transgenic mouse strain that enables the tracing of insulin-producing cells, we demonstrate that they arise dynamically from the ductal epithelium. Complementary work with human pancreatic slices suggests conservation of these mechanisms across species.