Expression of genes involved in thyroid hormone action in human induced pluripotent stem cells during differentiation to insulin-producing cells: Effects of iopanoic acid on differentiation

Aims: Type 3 iodothyronine deiodinase (Dio3) converts triiodothyronine (T3) to diiodothyronine, thereby reducing intracellular T3 levels. In this study, we investigated the potential roles of Dio3 in the differentiation of human pancreatic beta cells, using beta cells derived from human induced pluripotent stem cells (hiPSCs). Main methods: hiPSCs were differentiated to beta cells in a stepwise manner over 29 days. The differentiation medium was supplemented with B27, which contains T3 but not T4, instead of serum. The T3 levels in the differentiated cells were determined based on the amount of T3 supplied to the medium and the activity of Dio3 within the cells. Iopanoic acid (IOP) was used as the Dio3 inhibitor. Key findings: Dio3 expression is substantially altered during differentiation. IOP treatment reduced Dio3 activity on day 4 and increased T3 levels in the medium on day 29. To investigate the involvement of Dio3 during differentiation, we used IOP, in which cells differentiated in the presence of IOP (+IOP) were compared to those differentiated without IOP (-IOP). On day 29, the proportion of beta cells expressing C-peptide, NKX6 homeobox 1, and both markers was considerably higher in the presence than in the absence of IOP. Furthermore, on day 29, the insulin content of differentiated + IOP cells was considerably higher than that of differentiated-IOP cells. Conclusions: An increase in intracellular T3 content promoted via the inhibition of Dio3 activity by IOP from day 0-29 enhances the differentiation of hiPSCs to beta cells.