Pluripotency-independent induction of human trophoblast stem cells from fibroblasts

Human trophoblast stem cells (hTSCs) can be derived from embryonic stem cells (hESCs) or be induced from somatic cells by OCT4, SOX2, KLF4 and MYC (OSKM). Here we explore whether the hTSC state can be induced independently of pluripotency, and what are the mechanisms underlying its acquisition. We identify GATA3, OCT4, KLF4 and MYC (GOKM) as a combination of factors that can generate functional hiTSCs from fibroblasts. Transcriptomic analysis of stable GOKM- and OSKM-hiTSCs reveals 94 hTSC-specific genes that are aberrant specifically in OSKM-derived hiTSCs. Through time-course-RNA-seq analysis, H3K4me2 deposition and chromatin accessibility, we demonstrate that GOKM exert greater chromatin opening activity than OSKM. While GOKM primarily target hTSC-specific loci, OSKM mainly induce the hTSC state via targeting hESC and hTSC shared loci. Finally, we show that GOKM efficiently generate hiTSCs from fibroblasts that harbor knockout for pluripotency genes, further emphasizing that pluripotency is dispensable for hTSC state acquisition.

Automated summary

Researchers have discovered that GATA3, OCT4, KLF4, and MYC (GOKM) combination can generate functional human trophoblast stem cells (hiTSCs) from fibroblasts without the need for pluripotency. Through transcriptomic analysis, H3K4me2 deposition, and chromatin accessibility, it was found that GOKM exerts greater chromatin opening activity compared to OSKM. Additionally, GOKM efficiently generates hiTSCs from fibroblasts that lack pluripotency genes.