Pancreatic neurogenin 3-expressing cells are unipotent islet precursors

Abstract

Pancreatic islet endocrine cells arise during development from precursors expressing neurogenin 3 (Ngn3). As a population, Ngn3+ cells produce all islet cell types, but the potential of individual Ngn3+cells, an issue central to organogenesis in general and to in vitro differentiation towards cell-based therapies, has not been addressed. We performed in vivo clonal analyses in mice to study the proliferation and differentiation of very large numbers of single Ngn3+ cells using MADM, a genetic system in which a Cre-dependent chromosomal translocation labels, at extremely low mosaic efficiency, a small number of Ngn3+cells. We scored large numbers of progeny arising from single Ngn3+cells. In newborns, labeled islets frequently contained just a single tagged endocrine cell, indicating for the first time that each Ngn3+ cell is the precursor of a single endocrine cell. In adults, small clusters of two to three Ngn3+ progeny were detected, but all expressed the same hormone, indicating a low rate of replication from birth to adult stages. We propose a model whereby Ngn3+ cells are monotypic (i.e. unipotent)precursors, and use this paradigm to refocus ideas on how cell number and type must be regulated in building complete islets of Langerhans.