Cell-Cell Interactions in the Testis that Support Male Fertility

The testis has two important functions: the production of sperm for fertility and the synthesis and release of androgens, such as testosterone, that maintain sperm production, sexual function, health, and wellbeing. Sperm production takes place within the seminiferous tubules, supported by the somatic Sertoli cells, and is stimulated by gonadotrophins produced by the pituitary and androgens produced by the Leydig cells in the interstitium. Spermatogenesis is a highly complex and co-ordinated process regulated via cell-cell interactions between multiple cell types. Sertoli cells produce many factors, in a cyclic manner, that are required for germ cell development and, in turn, they receive signals from developing germ cells to maintain their function. Regulation of the spermatogenic cycle involves different cell types co-operating to produce a “pulse” of retinoic acid that stimulates immature germ cells to become committed to differentiation. Research in the past decade has shown that Sertoli cells do much more than regulate germ cell development; they maintain the development and function of peritubular myoid cells, the testicular vasculature and the Leydig cells. Sertoli cells send signals to interstitial immune cells to maintain an immunosuppressive environment and deposit thousands of proteins into the interstitium, including spermatid-specific proteins that likely help to promote peripheral immune tolerance. Leydig cells produce testosterone that acts on receptors in Sertoli cells to initiate and maintain spermatogenesis, and in peritubular myoid cells to support germ cell development. Leydig cells exist in a niche with specialised macrophages that can regulate Leydig cell function and steroidogenesis, highlighting that cross-talk between testis cells and the immune system is important for testis function. Defining the specific signals that operate between the different cell types that regulate key testis functions will help to uncover new therapies to support male fertility and testicular testosterone production over the life course.