Identification of apelin/APJ signaling dysregulation in a human iPSC-derived granulosa cell model of Turner syndrome

The interaction between germ cells and somatic cells in the ovaries plays a crucial role in establishing the follicle reserve in mammals. Turner syndrome (TS) predominantly occurs in females who have either a partial or complete loss of one of their X chromosomes. Our understanding of the role granulosa cells (GCs) play in TS disease progression and pathogenesis remains limited. Here, we elevated GC differentiation efficiency up to the level of 80% differentiated cells from iPSCs. In our attempt to replicate the differentiation process of embryonic granulosa cells, we observed that specific genes—GATA4, FOXL2, AMHR2, CYP19A1, and FSH—were downregulated in Turner syndrome-derived granulosa cells (TS-GCs). Additionally, dysregulation of the cell cycle was observed in TS-GCs. To reveal the endogenous defects in the TS-GCs, we conducted a comparison of the global transcriptome patterns between differentiated granulosa cells derived from iPSCs in both healthy and Turner syndrome groups. The apelin/APJ pathway displayed a differential between the healthy and TS groups. Supplementation of apelin ligands and activation of apelin/APJ downstream signals via Akt/PKB restored the cell cycle progression and marker gene expression. We hypothesize that during early embryonic development failures in apelin/APJ signaling in GCs in Turner syndrome patients leads to abnormalities in ovarian development and consequently to early loss of oocytes and infertility.