Retinoic acid specifically enhances embryonic stem cell metastate marked by Zscan4

Daniela Tagliaferri, Maria Teresa De Angelis, Nicola Antonino Russo, Maria Marotta, Michele Ceccarelli, Luigi Del Vecchio, Mario De Felice, Geppino Falco

Research output: Contribution to journalArticle

9 Citations (Scopus)


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.

Original languageEnglish
Article numbere0147683
JournalPLoS One
Issue number2
Publication statusPublished - 1 Feb 2016


ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Tagliaferri, D., De Angelis, M. T., Russo, N. A., Marotta, M., Ceccarelli, M., Del Vecchio, L., De Felice, M., & Falco, G. (2016). Retinoic acid specifically enhances embryonic stem cell metastate marked by Zscan4. PLoS One, 11(2), [e0147683].