Temporal activation of NR5A2 and RARγ induce functional human naïve pluripotent state via modulating TGFβ pathway

Rejuvenated primed human pluripotent stem cells, naïve cells, are accessible through the manipulating transcription factors, singaling pathways or a combination of both. However, there is a notable challenge in the functions of naïve hPSCs. Here, we show that the brief treatment with two chemical agonists (2a) of nuclear receptors NR5A2 and RARγ along with 2i and lif (2a2iL) is sufficient to induce naive pluripotency during the reprogramming of fibroblasts and pre-established hPSCs as well as the generation of new cell lines from preimplantation embryos. These cells manifested global naive-specific critera especially the contribution into the human-mouse chimeras. We demonstrated that TGF-β pathway activity is potentially critical for induction and maintenance of 2a2iL naive hPSCs. Consequently, transient activation of TGF-β resulted in generation of naive hPSCs in 2iL condition. These results represent a naive pluripotent state which is in a top point of developmental potential equivalent with preimplantation human embryo. Primed and naïve hESCs mRNA profiling in two cell lines.