Primordial Germ Cell Reprogramming

Abstract

Primordial germ cells (PGCs) are the embryonic precursors of the gametes. Thus, they are unipotent cells. However, PGCs share some common features with pluripotent stem cells. Among them, PGCs show alkaline phosphatase activity and express stage-specific embryonic antigens and pluripotency factors Lin28, Oct4, Sox2, and Nanog. Under specific conditions, they undergo spontaneous reprogramming in vivo. Moreover, they can be easily reprogrammed in vitro into pluripotent embryonic germ cells (EGCs) by culturing them in the presence of basic fibroblast growth factor or the epigenetic modulator trichostatin A. Previous work in our laboratory has also proven that hypoxia alone can reprogram PGCs into hypoxia-induced embryonic germ-like cells, which have a pluripotent phenotype but which do not show self-renewal capacity. Therefore, PGCs are an interesting model to further comprehensively understand the process of cell reprogramming. This chapter reviews various methods to achieve PGC reprogramming, as well as the molecular pathways involved. We focus on soluble factors and genetic strategies to obtain pluripotent cells from PGCs. Special emphasis will be given to factors implied in energetic metabolism, epigenetics, and cell signaling transduction, both in vitro and in vivo.

The Beginning of Meiosis in Mammalian Female Germ Cells: A Never-Ending Story of Intrinsic and Extrinsic Factors

“…The in vitro transdifferentiation of isolated premeiotic PGCs into pluripotent stem cells, termed EG cells, by specific cocktails of growth factors (KL, FGF2, LIF) or GSK3 and MAPK inhibitors (2i) [ 100 ] and the formation of Embryonal Carcinoma (EC) cells in vivo from undifferentiated PGCs [ 101 ] confirm the essential influence of signals from the fetal gonad environment on directing the correct germ-cell differentiation and meiosis. Moreover, these occurrences offer some clues on the processes that critically control the timely entering of PGCs into meiosis in fetal ovaries and into mitotic arrest in fetal testes.…”

“…These include KL/KIT-dependent PI3K/AKT pathways, PKA and ERK1/2 pathways, and PKCε, a novel DAG-dependent PKC. The manipulation of PGC epigenetics (i.e., the inhibition of deacetylation) or of signal transduction pathway components (i.e., the constitutive expression of AKT and the addition to the culture medium of FGF2, FRSK, PKCε inhibitor, or 2i) prevents the beginning of meiosis and makes both female and male PGCs prone to transdifferentiate in proliferating EG cells [ 100 ]. Interestingly, most of these molecular pathways seem to be present and active in human PGCs during the transition to premeiotic oogonia [ 102 ].…”