Embryonic Diapause as a Model for Pluripotent Stem Cell Quiescence

Abstract

Pluripotent stem cells inhabit, and can transition between, distinct metastable states. Embryonic stem cells (ESC), derived from the pre-implantation inner cell mass (ICM) of mouse embryos, retain a relatively more primitive (or “naïve”) phenotypic and functional profile compared to “primed” pluripotent cells derived from the post-implantation epiblast. Based on the hypothesis that a physiological state of stem cell dormancy, known as diapause, might represent a novel pluripotent state, I characterized the transcriptional programs of pluripotent stem cells from: i) the ICM of pre-implantation embryos; ii) the epiblast of post-implantation embryos; and iii) the ICM of embryos induced to enter diapause. The results presented in this dissertation demonstrate significant differences in the molecular signatures of these states and define diapause as a distinct “quiescence-associated” pluripotent state. Using this information I constructed a “developmental yardstick” for pluripotent stem cells and found that the quiescence-associated pluripotent state can be modeled in vitro. My findings also point to Runx1 as a likely regulator of the quiescence-associated state and provide a roadmap for dissecting the molecular basis of stem cell quiescence.