Single-Cell Gene Expression Analysis of a Human ESC Model of Pancreatic Endocrine Development Reveals Different Paths to β-Cell Differentiation

TY - JOUR

T1 - Single-Cell Gene Expression Analysis of a Human ESC Model of Pancreatic Endocrine Development Reveals Different Paths to β-Cell Differentiation

AU - Petersen, Maja Borup Kjær

AU - Azad, Ajuna

AU - Ingvorsen, Camilla

AU - Hess, Katja

AU - Hansson, Mattias

AU - Grapin-Botton, Anne

AU - Honoré, Christian

PY - 2017

Y1 - 2017

N2 - The production of insulin-producing β cells from human embryonic stem cells (hESCs) in vitro represents a promising strategy for a cell-based therapy for type 1 diabetes mellitus. To explore the cellular heterogeneity and temporal progression of endocrine progenitors and their progeny, we performed single-cell qPCR on more than 500 cells across several stages of in vitro differentiation of hESCs and compared them with human islets. We reveal distinct subpopulations along the endocrine differentiation path and an early lineage bifurcation toward either polyhormonal cells or β-like cells. We uncover several similarities and differences with mouse development and reveal that cells can take multiple paths to the same differentiation state, a principle that could be relevant to other systems. Notably, activation of the key β-cell transcription factor NKX6.1 can be initiated before or after endocrine commitment. The single-cell temporal resolution we provide can be used to improve the production of functional β cells. In this article, Honoré, Grapin-Botton, and colleagues use single-cell expression profiling to show a differentiation sequence from hESCs to pancreatic endocrine cells and early divergence of paths to different endocrine subtypes. Two paths lead to β-cell differentiation where NKX6.1 can be initiated before or after endocrine commitment.

AB - The production of insulin-producing β cells from human embryonic stem cells (hESCs) in vitro represents a promising strategy for a cell-based therapy for type 1 diabetes mellitus. To explore the cellular heterogeneity and temporal progression of endocrine progenitors and their progeny, we performed single-cell qPCR on more than 500 cells across several stages of in vitro differentiation of hESCs and compared them with human islets. We reveal distinct subpopulations along the endocrine differentiation path and an early lineage bifurcation toward either polyhormonal cells or β-like cells. We uncover several similarities and differences with mouse development and reveal that cells can take multiple paths to the same differentiation state, a principle that could be relevant to other systems. Notably, activation of the key β-cell transcription factor NKX6.1 can be initiated before or after endocrine commitment. The single-cell temporal resolution we provide can be used to improve the production of functional β cells. In this article, Honoré, Grapin-Botton, and colleagues use single-cell expression profiling to show a differentiation sequence from hESCs to pancreatic endocrine cells and early divergence of paths to different endocrine subtypes. Two paths lead to β-cell differentiation where NKX6.1 can be initiated before or after endocrine commitment.

KW - differentiation

KW - endocrine

KW - hormone

KW - lineage

KW - NEUROG3

KW - pancreas

KW - pluripotent stem cells

KW - progenitor

U2 - 10.1016/j.stemcr.2017.08.009

DO - 10.1016/j.stemcr.2017.08.009

M3 - Journal article

C2 - 28919263

AN - SCOPUS:85029423906

SN - 2213-6711

VL - 9

SP - 1246

EP - 1261

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 4

ER -