Biology and Pathology of the Oocyte: In vitro differentiation of germ cells from stem cells

Introduction Germ cells are the only cell type in the body that can carry genetic information on to the next generation, and the somatic cell lineages give rise to the soma, or body [1]. The development of germ cells from primordial germ cells (PGCs) into mature gametes involves a series of complex biological processes that occur over a given time period and that can be subdivided into several steps: specification, migration, epigenetic reprogramming, sex differentiation, and meiosis, the last of which includes oogenesis or spermatogenesis. A complex program of genetic regulatory networks rigorously directs the precise sequence of developmental events. Some genes are expressed specifically in germ cells, whereas others are expressed specifically in the somatic component of the germ cell environment. Yet still others are expressed in both germ cells and somatic cells. Despite recognizing the importance of germ cells, the scientific community has not yet elucidated the molecular mechanisms underlying the individual steps of germ cell development – these remain poorly understood, owing in part to the lack of sufficient tools and quantities of cells for conclusive studies. Embryonic stem cells (ESCs) are cells derived from the inner cell mass (ICM) of preimplantation blastocysts [2–4]. These cells have the ability to self-renew indefinitely while maintaining the feature of pluripotency, defined as the potential to differentiate into cell types of all three germ layers (ectoderm, endoderm, and mesoderm) and germ cells. The establishment of mouse ESCs (mESCs) and human ESCs (hESCs) brought great excitement not only to the scientific community, but also to the clinical setting, raising high expectations on the potential use of these cells to broaden our understanding of the mechanisms involved in development and disease. However, the controversy surrounding the derivation of ESCs from “human embryos” has limited the number of cell lines that could be derived. A breakthrough in the mid 2000s forever changed the field of stem cell research and has the potential to overcome this limitation. Somatic cells were discovered to be capable of being reprogrammed into so-called induced pluripotent stem cells (iPSCs) [5, 6] by the ectopic co-expression of the four transcription factors Oct4, Sox2, Klf4, and c-Myc – four factors that are known to sustain pluripotency in ESCs. This new technique enables the derivation of patient-specific iPSCs for disease modeling, drug screening, and investigations into the causative mechanisms underlying disease.