Tracing the cellular basis of islet specification in mouse pancreas

Magdalena K Sznurkowska,Roberta Azzarelli,Anna Philpott,Shosei Yoshida,Benjamin D Simons,Tatsuro Ikeda,Edouard Hannezo,Lemonia Chatzeli

doi:10.1038/s41467-020-18837-3

Abstract

Pancreatic islets play an essential role in regulating blood glucose level. Although the molecular pathways underlying islet cell differentiation are beginning to be resolved, the cellular basis of islet morphogenesis and fate allocation remain unclear. By combining unbiased and targeted lineage tracing, we address the events leading to islet formation in the mouse. From the statistical analysis of clones induced at multiple embryonic timepoints, here we show that, during the secondary transition, islet formation involves the aggregation of multiple equipotent endocrine progenitors that transition from a phase of stochastic amplification by cell division into a phase of sublineage restriction and limited islet fission. Together, these results explain quantitatively the heterogeneous size distribution and degree of polyclonality of maturing islets, as well as dispersion of progenitors within and between islets. Further, our results show that, during the secondary transition, α- and β-cells are generated in a contemporary manner. Together, these findings provide insight into the cellular basis of islet development.

Highlights

Pancreatic islets play an essential role in regulating blood glucose level
We show that, during the secondary transition, islet formation involves the aggregation of multiple equipotent endocrine progenitors that expand by stochastic proliferation after which they enter a phase of sublineage restriction and limited islet fission
We quantified the islet cell content of individual clones at postnatal day (P)[14], when commitment of cells to the pancreatic sublineages is thought to be complete[20], using 3D tissue reconstructions derived from thick serial sections stained for the islet marker Chromogranin A

Summary

Introduction

Pancreatic islets play an essential role in regulating blood glucose level. the molecular pathways underlying islet cell differentiation are beginning to be resolved, the cellular basis of islet morphogenesis and fate allocation remain unclear. From the statistical analysis of clones induced at multiple embryonic timepoints, here we show that, during the secondary transition, islet formation involves the aggregation of multiple equipotent endocrine progenitors that transition from a phase of stochastic amplification by cell division into a phase of sublineage restriction and limited islet fission Together, these results explain quantitatively the heterogeneous size distribution and degree of polyclonality of maturing islets, as well as dispersion of progenitors within and between islets. Transcriptomic analyses and 3D imaging of the embryonic day (E)13.5–E14.5 pancreas suggested that a temporally graded differentiation of Ngn3+ progenitors, occurring first into the α and the β-cell sublineage, could explain the mantle–core structure of mature islets[17] Whether this temporal gradient in α- and β-cell production persists during later stages of development remains unclear. We combine unbiased and targeted genetic lineage tracing strategies using mouse models based on a Rosa[26] (R26) and

Methods

Results

Conclusion