Pluripotency-independent induction of human trophoblast stem cells from fibroblasts.

Naama, Moriyah; Rahamim, Moran; Zayat, Valery; Sebban, Shulamit; Radwan, Ahmed; Orzech, Dana; Lasry, Rachel; Ifrah, Annael; Jaber, Mohammad; Sabag, Ofra; Yassen, Hazar; Khatib, Areej; Epsztejn-Litman, Silvina; Novoselsky-Persky, Michal; Makedonski, Kirill; Deri, Noy; Goldman-Wohl, Debra; Cedar, Howard; Yagel, Simcha; Eiges, Rachel

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. In this work Naama et al. describe and deeply characterize a direct approach to produce human induced trophoblast stem cells from fibroblasts and show that it produces superior hiTSCs when compared to OSKM-hiTSCs.

HUMAN stem cells; FIBROBLASTS; EMBRYONIC stem cells; TROPHOBLAST; SOMATIC cells; STEM cells

Nature Communications, 2023, Vol 14, Issue 1, p1

2041-1723

Academic Journal

10.1038/s41467-023-39104-1