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 Eiges and Yosef Buganim ()
Additional contact information
Moriyah Naama: The Hebrew University-Hadassah Medical School
Moran Rahamim: The Hebrew University-Hadassah Medical School
Valery Zayat: Polish Academy of Sciences
Shulamit Sebban: The Hebrew University-Hadassah Medical School
Ahmed Radwan: The Hebrew University-Hadassah Medical School
Dana Orzech: The Hebrew University-Hadassah Medical School
Rachel Lasry: The Hebrew University-Hadassah Medical School
Annael Ifrah: The Hebrew University-Hadassah Medical School
Mohammad Jaber: The Hebrew University-Hadassah Medical School
Ofra Sabag: The Hebrew University-Hadassah Medical School
Hazar Yassen: The Hebrew University-Hadassah Medical School
Areej Khatib: The Hebrew University-Hadassah Medical School
Silvina Epsztejn-Litman: Medical Genetics Institute, Shaare Zedek Medical Center
Michal Novoselsky-Persky: Hadassah-Hebrew University Medical Center
Kirill Makedonski: The Hebrew University-Hadassah Medical School
Noy Deri: The Hebrew University-Hadassah Medical School
Debra Goldman-Wohl: Hadassah-Hebrew University Medical Center
Howard Cedar: The Hebrew University-Hadassah Medical School
Simcha Yagel: Hadassah-Hebrew University Medical Center
Rachel Eiges: Medical Genetics Institute, Shaare Zedek Medical Center
Yosef Buganim: The Hebrew University-Hadassah Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39104-1

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