Competition for mitogens regulates spermatogenic stem cell homeostasis in an open niche

In many tissues, homeostasis is maintained by physical contact between stem cells and an anatomically-defined niche. However, how stem cell homeostasis is achieved in environments where cells are motile and dispersed among their progeny remains unknown. Using murine spermatogenesis as a model, we find that spermatogenic stem cell density is tightly regulated by the supply of fibroblast growth factors (FGFs) from lymphatic endothelial cells. We propose that stem cell homeostasis is achieved through competition for a limited supply of FGFs. We show that the quantitative dependence of stem cell density on FGF dosage, the biased localization of stem cells toward FGF sources, and stem cell dynamics during regeneration following injury can all be predicted and explained within the framework of a minimal theoretical model based on “mitogen competition”. We propose that this model provides a generic and robust mechanism to support stem cell homeostasis in open, or facultative, niche environments. To understand the impact of FGF5 for in vitro spermatogonia, the gene expression profiles on in vitro cultured spermatogonia with or without FGF5. Two independent experiments were performed using different biological samples. To understand the impact of Fgf5 for in vivo GFRα1+ spermatogonia, the gene expression profiles on GFRα1+ spermatogonia in wt and Fgf5–/– mice were measured. GFRα1+ spermatogonia were isolated by FACS from cell suspensions prepared from the testes of GFRα1-EGFP knock-in mice in wt and Fgf5–/– background. Three independent experiments were performed for wt and Fgf5–/–.