Spermatogonia: a unique stem cell orchestrating species-specific transition from pluripotency to sperm production.

Background: Male germline stem cells are relevant for stem cell researchers but also for andrologists as they are crucial for testis function and initiation/maintenance of spermatogenesis. They are also considered a target for fertility preservation in the male; e.g. germ cell transplantation or testicular grafting rely on spermatogonial stem cells (SSCs) and may soon become clinical tools to recover fertility. In the current review, we report new insights into genesis of spermatogonia, germline plasticity, and models of spermatogonial expansion. These insights and an array of novel cellular and molecular tools have provided great technological advances and new knowledge and therefore the field of SSCs needs an up-to-date review.

Objective: In this review, we focus on the male germline starting with pluripotent precursors and ending with sperm. The recent discoveries on mechanisms and cellular events involved in the derivation of SSCs are highlighted. We summarize all information on clonal expansion of SSCs in several species. We revisit old models and formulate novel models for the initial phases of spermatogenesis considering species-specific differences. Specifically, the human situation will be presented, informing the reader on many primate-specific features (i.e. the existence of self-renewing progenitors, limited premeiotic mitotic steps, and small clonal sizes). This review is important as the current view on spermatogonia in the human testis needs an update taking in novel and unexpected findings derived from studies using new technologies, such as microfluidics, single-cell analysis, and xenografting. These findings also require re-interpretations of previously published results and models for spermatogonial function.

Search Methods: We used PubMed and other relevant databases to reveal all available information. Search terms were flexibly combined. Baseline search terms were: spermatogonia/testis/stem cell/mitotic expansion/clone/primate/human/spermatogenesis/meiotic entry/germ cell niche/sperm production/spermatogenic efficiency.

Outcomes: Spermatogenesis in men relies on a stem cell system which is highly distinct from that of rodents. Derivation of spermatogonia from pluripotent precursors has been explored in approaches using embryonic stem cells and induced pluripotent stem cells leading to novel concepts which are highlighted. The testis is populated with five subpopulations of premeiotic germ cells with specific tasks and functions. We will specifically focus on these features in this review. Based on the internal or external stimuli received from the microenvironment through underlying signalling and regulatory networks, subpopulations may show diverse responses. The high plasticity and variable potency of spermatogonial populations may play an important and distinct role during normal or aberrant germline developments alike. SSC models are helpful tools to understand the rigorous checkpoints maintaining germline quality at pre-meiotic and meiotic stages. Evidence from calculated spermatogonial ratios for various species indicates that clonal expansion rates are slower in higher primates like macaques and humans. In contrast, clonal expansion takes place at a faster rate in small animals like rodents. The consequences of these species-specific differences in germline development are discussed. Further options for future clinical applications and new therapies are also discussed in this review.

Wider Implications: Our revised understanding of the SSCs and their somatic niches creates a novel view on the causes of male infertility and may open strategies not only for curative actions but also for fertility preservation and ex vivo strategies to generate spermatozoa.