title: Retinoic Acid Specifically Enhances Embryonic Stem Cell Metastate Marked by Zscan4.
abstract: Pluripotency confers Embryonic Stem Cells (ESCs) the ability to differentiate in ectoderm, endoderm, and mesoderm derivatives, producing the majority of cell types. Although the majority of ESCs divide without losing pluripotency, it has become evident that ESCs culture consists of multiple cell populations with different degrees of potency that are spontaneously induced in regular ESC culture conditions. Zscan4, a key pluripotency factor, marks ESC subpopulation that is referred to as high-level of pluripotency metastate. Here, we report that in ESC cultures treated with retinoic acid (RA), Zscan4 ESCs metastate is strongly enhanced. In particular, we found that induction of Zscan4 metastate is mediated via RA receptors (RAR-alpha, RAR-beta, and RAR-gamma), and it is dependent on phosphoinositide-3-kinase (PI3K) signaling. Remarkably, Zscan4 metastate induced by RA lacks canonical pluripotency genes Oct3/4 and Nanog but retained both self-renewal and pluripotency capabilities. Finally we demonstrated that the conditional ablation of Zscan4 subpopulation is dispensable for both endoderm and mesoderm but is required for ectoderm lineage. In conclusion, our research provides new insights about the role of RA signaling during ESCs high pluripotency metastate fluctuation.
authors: Biogem, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy.
authors: Daniela
authors: D
authors: Tagliaferri
authors: Biogem, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy.
authors: Maria Teresa
authors: MT
authors: De Angelis
authors: Biogem, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy.
authors: Nicola Antonino
authors: NA
authors: Russo
authors: Biogem, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy.
authors: Maria
authors: M
authors: Marotta
authors: Qatar Computing Research Institute, HBKU, Doha, Qatar.
authors: Michele
authors: M
authors: Ceccarelli
authors: Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy.
authors: Luigi
authors: L
authors: Del Vecchio
authors: Biogem, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy.|Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy.
authors: Mario
authors: M
authors: De Felice
authors: Biogem, Istituto di Ricerche Genetiche Gaetano Salvatore Biogem scarl, Ariano Irpino, Italy.|Department of Science, Università degli Studi del Sannio, Benevento, Italy.|Department of Biology, University of Naples "Federico II", Naples, Italy.
authors: Geppino
authors: G
authors: Falco
mesh_terms: D002460:Cell Line; D000066673:Cell Self Renewal / Q000235:genetics; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D004707:Endoderm / Q000378:metabolism; D020869:Gene Expression Profiling; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D014212:Tretinoin; D019869:Phosphatidylinositol 3-Kinases