XEN and the Art of Stem Cell Maintenance: Molecular Mechanisms Maintaining Cell Fate and Self-Renewal in Extraembryonic Endoderm Stem (XEN) Cell Lines

Abstract

The extraembryonic endoderm is one of the first cell types specified during mammalian development. This extraembryonic lineage is known to play multiple important roles throughout mammalian development, including guiding axial patterning and inducing formation of the first blood cells during embryogenesis. Moreover, recent studies have uncovered striking conservation between mouse and human embryos during the stages when extraembryonic endoderm cells are first specified, in terms of both gene expression and morphology. Therefore, mouse embryos serve as an excellent model for understanding the pathways that maintain extraembryonic endoderm cell fate. In addition, self-renewing multipotent stem cell lines, called XEN cells, have been derived from the extraembryonic endoderm of mouse embryos. Mouse XEN cell lines provide an additional tool for understanding the basic mechanisms that contribute to maintaining lineage potential, a resource for identifying how extraembryonic ectoderm specifies fetal cell types, and serve as a paradigm for efforts to establish human equivalents. Given the potential conservation of essential extraembryonic endoderm roles, human XEN cells would provide a considerable advance. However, XEN cell lines have not yet been successfully derived from human embryos. Given the potential utility of human XEN cell lines, this chapter focuses on reviewing the mechanisms known to govern the stem cell properties of mouse XEN, in hopes of facilitating new ways to establish human XEN cell lines.