The Millman Lab had their article published May 26 in Cell Reports. In their research, they discovered that the transcription factor SIX2 is essential for the functional maturation of stem cell-derived beta cells. This is important as the lab team continues to engineer these cells for diabetes cell replacement therapy.
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 they 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. The researchers’ results demonstrate that expression of SIX2 influences the generation of human SC-β cells in vitro.