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  • Temporal activation of LRH-1 and RAR-γ in human pluripotent stem cells induces a functional naïve-like state.

Temporal activation of LRH-1 and RAR-γ in human pluripotent stem cells induces a functional naïve-like state.

EMBO reports (2020-12-01)
Adeleh Taei, Tahereh Kiani, Zeinab Taghizadeh, Sharif Moradi, Azam Samadian, Sepideh Mollamohammadi, Ali Sharifi-Zarchi, Stefan Guenther, Azimeh Akhlaghpour, Behrouz Asgari Abibeiglou, Mostafa Najar-Asl, Razieh Karamzadeh, Keynoosh Khalooghi, Thomas Braun, Seyedeh-Nafiseh Hassani, Hossein Baharvand
ABSTRACT

Naïve pluripotency can be established in human pluripotent stem cells (hPSCs) by manipulation of transcription factors, signaling pathways, or a combination thereof. However, differences exist in the molecular and functional properties of naïve hPSCs generated by different protocols, which include varying similarities with pre-implantation human embryos, differentiation potential, and maintenance of genomic integrity. We show here that short treatment with two chemical agonists (2a) of nuclear receptors, liver receptor homologue-1 (LRH-1) and retinoic acid receptor gamma (RAR-γ), along with 2i/LIF (2a2iL) induces naïve-like pluripotency in human cells during reprogramming of fibroblasts, conversion of pre-established hPSCs, and generation of new cell lines from blastocysts. 2a2iL-hPSCs match several defined criteria of naïve-like pluripotency and contribute to human-mouse interspecies chimeras. Activation of TGF-β signaling is instrumental for acquisition of naïve-like pluripotency by the 2a2iL induction procedure, and transient activation of TGF-β signaling substitutes for 2a to generate naïve-like hPSCs. We reason that 2a2iL-hPSCs are an easily attainable system to evaluate properties of naïve-like hPSCs and for various applications.

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