Reconstructing human pancreatic differentiation by mapping specific cell populations during development.

Cyrille Ramond,Christian Honoré,Henrik Semb,Raphaël Scharfmann,Nicolas Glaser,Claire Berthault,Jeannette Schlichting Kirkegaard,Jacqueline Ameri,Mattias Hansson

doi:10.7554/elife.27564

Abstract

Information remains scarce on human development compared to animal models. Here, we reconstructed human fetal pancreatic differentiation using cell surface markers. We demonstrate that at 7weeks of development, the glycoprotein 2 (GP2) marks a multipotent cell population that will differentiate into the acinar, ductal or endocrine lineages. Development towards the acinar lineage is paralleled by an increase in GP2 expression. Conversely, a subset of the GP2+ population undergoes endocrine differentiation by down-regulating GP2 and CD142 and turning on NEUROG3, a marker of endocrine differentiation. Endocrine maturation progresses by up-regulating SUSD2 and lowering ECAD levels. Finally, in vitro differentiation of pancreatic endocrine cells derived from human pluripotent stem cells mimics key in vivo events. Our work paves the way to extend our understanding of the origin of mature human pancreatic cell types and how such lineage decisions are regulated.

Highlights

Intensive efforts are currently dedicated towards the development of cell replacement therapies using cell types derived from human pluripotent stem cells
We demonstrate that at 7weeks of development, the glycoprotein 2 (GP2) marks a multipotent cell population that will differentiate into the acinar, ductal or endocrine lineages
By mirroring the hematopoietic field, we developed here an approach where cell surface markers are used to recapitulate the hierarchical sequence of human pancreatic development

Summary

Introduction

Intensive efforts are currently dedicated towards the development of cell replacement therapies using cell types derived from human pluripotent stem cells (hPSC). Human insulin-producing beta cells represent a paradigm for this type of objective. These cells have a major physiological function, regulating circulating glucose levels by producing and secreting insulin. In patients suffering from type one diabetes, these cells are destroyed by an autoimmune mechanism, and would need to be replaced (Benthuysen et al, 2016). Beta cell replacement holds immense promises for diabetic patients and current strategies have reached major milestones (Pagliuca et al, 2014; Russ et al, 2015; Rezania et al, 2014). It is well accepted that a more detailed understanding of beta cell development in human is required to generate unlimited functional human beta cells (Johnson, 2016)

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