Roadmap of germline development and in vitro gametogenesis from pluripotent stem cells

Abstract

Background: The germ cell lineage is a fundamental component of the metazoan life cycle, ensuring the perpetuation and substantial diversification of genetic information across generations. Recent advances in the understanding of mouse germ cell development have culminated in the ability to reconstitute gametogenesis in vitro, thereby enabling the biochemical and molecular analyses of germ cell specification and subsequent development in mice. Similar advances in reconstituting human germ cells in vitro would provide critical insight into the etiology of various reproductive conditions and disorders, including infertility.

Objectives: This review presents the mechanisms leading to germ cell development in mammals, particularly in mice and non-human primates, as well as the applicability of these animal models to human germ cell development. The induction methods performed to recapitulate germ cell development in vitro are also discussed in this review, specifically focusing on in vitro gametogenesis from pluripotent stem cells.

Materials and methods: This review compiles the key methods and findings of various references relevant to the above-mentioned topic.

Results: Murine models have provided essential mechanistic insight into the process of germ cell lineage development. However, there are several structural differences between mice and humans during early embryogenesis that hinder the extrapolation of findings made in murine models to what may occur in humans. Recent studies using human or non-human primate embryos and human-induced pluripotent stem cell (hiPSC)-derived germ cells shed light on key cellular and genetic mechanisms governing germ cell development in humans.

Discussion: Utilizing the knowledge obtained from studying germ cell development in different animal models, induction methods established by various laboratories now permit partial reconstitution of human gametogenesis in vitro.

Conclusion: In vitro gametogenesis will constitute an emergent new field in human reproductive medicine in the near future, although legal and ethical considerations must be taken into account.

Keywords: PGC specification; amniogenesis; human primordial germ cell-like cells; in vitro gametogenesis; primordial germ cells; spermatogenesis.