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Temporal activation of LRH-1 and RAR-gamma in human pluripotent stem cells induces a functional naive-like state

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Guenther,  Stefan
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Khalooghi,  Keynoosh
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Braun,  Thomas
Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Taei, A., Kiani, T., Taghizadeh, Z., Moradi, S., Samadian, A., Mollamohammadi, S., et al. (2020). Temporal activation of LRH-1 and RAR-gamma in human pluripotent stem cells induces a functional naive-like state. EMBO REPORTS, 21(10): e47533. doi:10.15252/embr.201847533.


Cite as: https://hdl.handle.net/21.11116/0000-0007-4EAB-2
Abstract
Naive 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 naive 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-gamma), along with 2i/LIF (2a2iL) induces naive-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 naive-like pluripotency and contribute to human-mouse interspecies chimeras. Activation of TGF-beta signaling is instrumental for acquisition of naive-like pluripotency by the 2a2iL induction procedure, and transient activation of TGF-beta signaling substitutes for 2a to generate naive-like hPSCs. We reason that 2a2iL-hPSCs are an easily attainable system to evaluate properties of naive-like hPSCs and for various applications.