Role of the testis interstitial compartment in spermatogonial stem cell function

Intricate cellular and molecular interactions ensure that spermatogonial stem cells (SSCs) proceed in a step-wise differentiation process through spermatogenesis and spermiogenesis to produce sperm. SSCs lie within the seminiferous tubule compartment, which provides a nurturing environment for the development of sperm. Cells outside of the tubules, such as interstitial and peritubular cells, also help direct SSC activity. This review focuses on interstitial (interstitial macrophages, Leydig cells and vasculature) and peritubular (peritubular macrophages and peritubular myoid cells) cells and their role in regulating the SSC self-renewal and differentiation in mammals. Leydig cells, the major steroidogenic cells in the testis, influence SSCs through secreted factors, such as insulin growth factor 1 (IGF1) and colony-stimulating factor 1 (CSF1). Macrophages interact with SSCs through various potential mechanisms, such as CSF1 and retinoic acid (RA), to induce the proliferation or differentiation of SSCs respectively. Vasculature influences SSC dynamics through CSF1 and vascular endothelial growth factor (VEGF) and by regulating oxygen levels. Lastly, peritubular myoid cells produce one of the most well-known factors that is required for SSC self-renewal, glial cell line-derived neurotrophic factor (GDNF), as well as CSF1. Overall, SSC interactions with interstitial and peritubular cells are critical for SSC function and are an important underlying factor promoting male fertility.