Testicular macrophages are recruited during a narrow time window by fetal Sertoli cells to promote organ-specific developmental functions

Abstract

While macrophages are most commonly known for their roles in innate immunity, a growing body of evidence supports the idea that fetal-derived tissue-resident macrophages play developmental roles during organogenesis. In the testis, it has long been proposed that macrophages are important players in steroidogenesis and other testicular functions, but which macrophage populations are involved is unclear. We previously showed that macrophages play critical roles in fetal testis morphogenesis and reported the presence of 2 unique adult testicular macrophage populations, interstitial and peritubular. There has been some debate regarding the hematopoietic origins of testicular macrophages and whether distinct macrophage populations promote specific testicular functions. Here we have undertaken an extensive lineage-tracing study of mouse hematopoietic cells. We found that, while yolk-sac-derived macrophages comprise the earliest testicular macrophages, fetal hematopoietic stem cells (HSCs) give rise to monocytes that colonize the gonad during a narrow time window in mid-gestation, after which time HSCs no longer contribute to testicular macrophages. These long-lived monocytes, over the course of fetal and postnatal life, differentiate into testicular macrophages. Our data indicate that Sertoli cells, and not germ cells, are required for recruitment of immune cells and peritubular macrophage differentiation. Finally, we show that yolk-sac-derived macrophages and HSC-derived macrophages play distinct roles in testis cord morphogenesis, whereas interstitial macrophages promote adult Leydig cell proliferation and steroid production. Overall, our findings offer clarity regarding the origins of testicular macrophages and provide insight into the diversity of their tissue-specific developmental roles.