In or out stemness: comparing growth factor signalling in mouse embryonic stem cells and primordial germ cells

Embryonic stem (ES) cells do not exist in nature but, usually produced from the inner cell mass (ICM) of the blastocyst, are considered equivalent to ICM cells captured during a short period of transient self-renewal and pluripotency capability. Although, artificial, ES cells represent a formidable model to investigate fundamental aspects of cell stemness and early embryo development. ES cells are indeed the only stem cell type able to indefinite self-renewal and to differentiate into cellular derivates of ectodermal, mesodermal and endodermal lineages. Recent extensive studies have revealed that ES cells maintain self-renewal and pluripotency because of a self-organizing network of transcription factors and intracellular pathways activated by extracellular signalling that together prevent their differentiation and promote their proliferation, and because of epigenetic processes that maintain the chromatin in a plastic differentiation status. Primordial germ cells (PGCs), the embryonic precursors of gametes, because of their unique ability to retain true developmental totipotency, are considered the mother of all stem cells. Despite several similarities with ES cells, they display only transient self-renewal capability and distinct lineage-specific characteristics. In fact, in normal condition PGCs are believed to differentiate into germ cells only, oogonia/oocytes in the female, and prospermatogonia in the male which ultimately produce eggs and sperm, respectively. It is not until the fertilization of the egg or parthenogenesis that the intrinsic germ cell totipotency program is revealed. Many aspects of the extrinsic factors and signalling required for ES cell self-renewal and pluripotency have been identified and dissected. On the other hand, several extrinsic factors controlling PGC development have been identified, but the underlying molecular signalling remains little defined. In the present review, by comparing the available information about signalling elicited by four growth factors such as leukaemia inhibitory factor (LIF), bone morphogenic protein 4 (BMP4), fibroblast growth factor 2 (FGF2) and kit ligand (KL) in mouse ES cells and PGCs, on which most of such studies have been performed, we aimed to give clues for the molecular understanding of the similarities and differences between these two unique cell types and to explain how apparent contradictory properties such as lineage-specific characteristics and pluripotency may coexist within PGCs. The first two growth factors have been demonstrated to control key aspects of the self-renewal and pluripotency of ES cells. BMP4 and KL are known for their crucial role in regulating various process of PGC development in the embryo from the formation of PGC precursors and PGC specification (BMP4) to their survival, proliferation and migration (KL). Moreover, the combined action of LIF, FGF2 and KL is necessary and sufficient for PGC transformation into ES-like cells termed embryonic germ (EG) cells.