May 28, 2020

SIX2 Regulates Human β Cell Differentiation from Stem Cells and Functional Maturation In Vitro

Cell Reports
Leonardo Velazco-CruzJeffrey R Millman

Abstract

Generation of insulin-secreting β cells in vitro is a promising approach for diabetes cell therapy. Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) are differentiated to β cells (SC-β cells) and mature to undergo glucose-stimulated insulin secretion, but molecular regulation of this defining β cell phenotype is unknown. Here, we show that maturation of SC-β cells is regulated by the transcription factor SIX2. Knockdown (KD) or knockout (KO) of SIX2 in SC-β cells drastically limits glucose-stimulated insulin secretion in both static and dynamic assays, along with the upstream processes of cytoplasmic calcium flux and mitochondrial respiration. Furthermore, SIX2 regulates the expression of genes associated with these key β cell processes, and its expression is restricted to endocrine cells. Our results demonstrate that expression of SIX2 influences the generation of human SC-β cells in vitro.

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Mentioned in this Paper

Respiration
Stimulation of Insulin Secretion
Gene Knockdown Techniques
MRNA Maturation
Mice, Knockout
SIX2 gene
Cytoplasm
Transcription Factor
SIX2
Diabetes

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