Differentiation of uniparental human embryonic stem cells into granulosa cells reveals a paternal contribution to gonadal development

Genomic imprinting underlies the mammalian requirement for sexual reproduction. Nonetheless, the relative contribution of the two parental genomes during human development is not fully understood. Specifically, a fascinating question is whether the formation of the gonad, which holds the ability to reproduce, depends on equal contribution from both parental genomes. Here, we differentiated andro-genetic and parthenogenetic human pluripotent stem cells (hPSCs) into ovarian granulosa-like cells (GLCs). We show that in contrast to biparental and androgenetic cells, parthenogenetic hPSCs present a reduced capacity to differentiate into GLCs. We further identify the paternally expressed gene IGF2 as the most upregulated imprinted gene upon differentiation. Remarkably, while IGF2 knockout andro-genetic cells fail to differentiate into GLCs, the differentiation of parthenogenetic cells supplemented with IGF2 is partly rescued. Thus, our findings unravel a surprising essentiality of genes that are only expressed from the paternal genome to the development of the female reproductive system.

Automated summary

This study investigates the relative contribution of parental genomes during human development, particularly focusing on whether the formation of the reproductive gonad depends on equal contribution from both parents. The researchers find that compared to biparental and androgenetic cells, parthenogenetic cells have a reduced ability to differentiate into ovarian granulosa-like cells (GLCs). They also identify the paternally expressed gene IGF2 as being highly upregulated during differentiation, and that the differentiation of parthenogenetic cells can be partly rescued by supplementing them with IGF2.