Human primordial germ cells and embryonic germ cells, and their use in cell therapy

Human embryonic germ (hEG) cells derive from the transformation of primordial germ cells (PGCs) under appropriate culture conditions with embryonic fibroblast feeder cells. Although the pluripotent and proliferative capacity of hEG cells is thought to be equivalent to that of human embryonic stem (hES) cells, the difficulties of isolating and maintaining hEG cell lines in vitro have restricted their availability for experimental use. Despite this, some of the factors involved in PGC development, their transformation into embryonic germ cells and the differentiation of embryonic germ cells to specific cell phenotypes have been explored. The potential use of hEG cells in cell therapy applications will, however, depend on a more thorough understanding of how to derive and maintain these cells in vitro.

Introduction

Embryonic germ (EG) cells result from the adaptation of primordial germ cells (PGCs) to survive and self-renew in culture [1, 2, 3]. They usually have a normal karyotype (initially at least), and display a pluripotency that enables differentiation into a wide range of tissue types of all three primary cell lineages either in vitro or on forming teratomas when transplanted to suitable sites of the body (i.e. to the testis or kidney capsule). Although human embryonic germ (hEG) cells were first derived [3] around the same time as their pluripotent counterparts, human embryonic stem (hES) cells [4], there has been far less attention focused on the potential use of hEG cells for applications in regenerative medicine than on the use of hES cells. The cause of this disparity is mainly twofold. First, although both stem cells are of controversial origin and their derivation necessitates comprehensive ethical and, in some countries, legislative approval, the recovery of PGCs from early human foetal tissue presents additional practical issues of timing (as tissue is recovered after termination of pregnancy) that can limit access to suitable samples to a greater extent than for obtaining pre-implantation embryos for hES cell derivation. Second, although the initial generation of hEG cells is relatively simple [5^•], the maintenance of well-defined cell lines through extended passage in culture has proved to be quite difficult to date [6•, 7•]. This has restricted the wide distribution of well-characterised hEG cell lines to investigators to explore potential cell therapies. Despite these problems, EG cells represent an important alternative to ES cells because they potentially have a different epigenetic status to hES cells that might ultimately prove to be significant for cell therapy applications (Table 1). Moreover, EG cells are important tools for studying factors involved in PGC survival, proliferation and regulation that have clinical relevance. For example, testicular cancer in men arises from carcinoma in situ cells, which probably originate from PGCs that escape normal differentiation processes as is also the case for EG cells [8]. In this review we examine some of the main factors involved in the specification and maintenance of PGCs in vivo and in vitro and the culture conditions that influence the derivation of EG cells. The potential of PGCs and EGs to undergo differentiation to functional cell types for clinical applications is also considered.