Although naïve and primed pluripotent states have some common features, there are considerable differences at the cellular and molecular levels. Both hPSCs and EpiSCs lack the ability to form chimeras (Brons et al, 2007 Tesar et al, 2007 Nichols & Smith, 2009). However, human PSCs (hPSCs) are in a primed state of pluripotency, similar to mouse post‐implantation epiblast‐derived stem cells (EpiSCs). Naïve PSCs can participate in embryo development to form chimeric organisms. In mice, both ESCs and iPSCs are the genuine counterparts of pre‐implantation epiblast cells. In vitro‐derived pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced PSCs (iPSCs), recapitulate numerous properties of epiblast cells (Evans & Kaufman, 1981 Martin, 1981 Thomson et al, 1998 Takahashi & Yamanaka, 2006). The epiblast of an early embryo is considered to contain bona fide in vivo pluripotent cells. Mammalian pluripotency is defined as the ability of a cell to differentiate into all the cell types of an adult organism. We reason that 2a2iL‐hPSCs are an easily attainable system to evaluate properties of naïve‐like hPSCs and for various applications. 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.
2a2iL‐hPSCs match several defined criteria of naïve‐like pluripotency and contribute to human–mouse interspecies chimeras. 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. 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. Naïve pluripotency can be established in human pluripotent stem cells (hPSCs) by manipulation of transcription factors, signaling pathways, or a combination thereof.
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