Pluripotency-independent induction of human trophoblast stem cells from fibroblasts

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageAmerican English
Article number3359
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - 8 Jun 2023

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Publisher Copyright:
© 2023, The Author(s).

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