Fetal macrophages mediate vascularization and cord formation during testis organogenesis

Abstract

During testis organogenesis, Sertoli cell progenitors undergo an unusual process of de novo organization to form testis cords. Sertoli cells are a driving force in the formation of these epithelial tubules, but reorganization of the vasculature and expansion of the stromal cells also play critical roles in testis cord morphogenesis. Experiments show that blocking vascular reorganization blocks the process of cord formation. Pdgf signaling from the endothelium to the surrounding stroma leads to the expansion of the interstitial cells between the cords, a process that subdivides the field of the gonad into cord-forming units. The gonad initially forms by proliferation of the coelomic epithelum overlying the mesonephros. Vascularization of the developing organ occurs by branching from a vascular bed at the border of the mesonephros and the emerging gonad. Interestingly, fetal macrophages derived from the yolk sac are associated with the vasculature during the initial phases of testis morphogenesis. We show that most gonadal macrophages exhibit hallmarks of M2 activation status, suggestive of angiogenic and tissue remodeling functions. Genetic or pharmacological depletion of macrophages disrupts the process of testis cord formation by blocking vascular reorganization at the mesonephric border. In addition, we show that macrophages are involved in pruning cells to refine testis architecture once the basic structure of cords is established. These findings reveal a previously unappreciated role for macrophages in testis morphogenesis as intermediaries between neovascularization and organ architecture during fetal organogenesis. We are grateful for funding from NICHD and NIGMS.