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SIX2 Regulates Human β Cell Differentiation from Stem Cells and Functional Maturation In Vitro
Leonardo Velazco-Cruz1, Madeleine M Goedegebuure1, Kristina G Maxwell2
1Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
Cell Reports
|May 28, 2020
Summary
The transcription factor SIX2 is crucial for maturing stem cell-derived beta cells. Its absence impairs glucose-stimulated insulin secretion, a key function for diabetes cell therapy.
Area of Science:
- Stem cell biology
- Endocrinology
- Molecular biology
Background:
- * Generating functional beta cells from stem cells is vital for diabetes cell therapy.
- * The molecular mechanisms controlling beta cell maturation remain largely unknown.
Purpose of the Study:
- * To identify key regulators of stem cell-derived beta cell (SC-β cell) maturation.
- * To investigate the role of transcription factor SIX2 in SC-β cell function.
Main Methods:
- * Used human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) to generate SC-β cells.
- * Employed SIX2 knockdown (KD) and knockout (KO) models.
- * Assessed glucose-stimulated insulin secretion, cytoplasmic calcium flux, and mitochondrial respiration.
Main Results:
- * SIX2 KD/KO significantly impaired glucose-stimulated insulin secretion in SC-β cells.
- * SIX2 deficiency reduced calcium flux and mitochondrial respiration.
- * SIX2 regulates genes critical for beta cell function and is expressed in endocrine cells.
Conclusions:
- * Transcription factor SIX2 is essential for the maturation and function of human SC-β cells.
- * SIX2 plays a critical role in enabling glucose-stimulated insulin secretion.
- * SIX2 is a key molecular regulator influencing the generation of functional SC-β cells in vitro.
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