Abstract
Human induced pluripotent stem cells (hiPSCs) are expected to be both a revolutionary cell source for regenerative medicine and a powerful tool to investigate the molecular mechanisms underlying human cell development in vitro. In the present study, we tried to elucidate the steroidogenic differentiation processes using hiPSC-derived intermediate mesoderm (IM) that is known to be the origin of the human adrenal cortex and gonads. We first performed chemical screening to identify small molecules that induce steroidogenic differentiation of IM cells expressing Odd-skipped related 1 (OSR1), an early IM marker. We identified cabergoline as an inducer of 3β-hydroxysteroid dehydrogenase, an essential enzyme for adrenogonadal steroidogenesis. Although cabergoline is a potent dopamine D2 receptor agonist, additional experiments showed that cabergoline exerted effects as a low-affinity agonist of D1 receptors by increasing intracellular cyclic AMP. Further analysis of OSR1+ cells transfected with steroidogenic factor-1/adrenal 4 binding protein revealed that D1 receptor agonist upregulated expression of various steroidogenic enzymes and increased secretion of steroid hormones synergistically with adrenocorticotropic hormone. These results suggest the importance of dopamine D1 receptor signalling in steroidogenic differentiation, which contributes to effective induction of steroidogenic cells from hiPSCs.
Highlights
Adrenal insufficiency occurs when the adrenal cortex fails to produce sufficient levels of steroid hormones, which are essential for our survival
To determine an appropriate marker indicating the induction of intermediate mesoderm (IM) cells into steroidogenic cells, we examined the mRNA expression of steroidogenic enzymes in Odd-skipped related 1 (OSR1)+ cells
Using a chemical screening method, the present study identified a compound, cabergoline, that increases 3β-HSD expression in OSR1+ IM cells
Summary
Adrenal insufficiency occurs when the adrenal cortex fails to produce sufficient levels of steroid hormones, which are essential for our survival. In 1997 Crawford et al first reported the induction of mouse embryonic stem cells into steroidogenic cells using forced expression of steroidogenic factor-1/adrenal 4 binding protein (SF-1/Ad4BP), known as a transcriptional master regulator of steroidogenic genes[11]. In 2012 we first reported the induction of both human embryonic stem cell (hESC)- and human induced pluripotent stem cell (hiPSC)-derived mesodermal cells into steroid-producing cells[17]. HPSCs are expected to be a cell source for regenerative medicine, and a powerful tool to investigate the molecular mechanisms underlying human cell development in vitro. For this aim, chemical screening has reportedly been a useful method. Araoka et al identified two compounds effective for differentiating hiPSCs/ESCs into IM cells[24]
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