Yolk-sac–derived macrophages regulate fetal testis vascularization and morphogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 23; p. 8329
• Main Authors: DeFalco, Tony, Bhattacharya, Indrashis, Williams, Alyna V., Sams, Dustin M., Capel, Blanche
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10-06-2014; National Acad Sciences
• Series: PNAS Plus
• Subjects: Animals; Biological Sciences; Cell Lineage; Cells; Cellular biology; CX3C Chemokine Receptor 1; Fetus - blood supply; Fetus - cytology; Fetus - embryology; Flow Cytometry; Gene expression; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Hematopoietic Stem Cells - metabolism; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Confocal; Morphogenesis; Myeloid Cells - metabolism; Organ Culture Techniques; PNAS Plus; PNAS Plus: Significance Statements; Receptors, Chemokine - genetics; Receptors, Chemokine - metabolism; Testis - blood supply; Testis - cytology; Testis - embryology; Time Factors; Yolk Sac - metabolism; myeloid cell; mononuclear phagocyte; VEGF; endothelial cell; sex determination
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1400057111

Organogenesis of the testis is initiated when expression of Sry in pre-Sertoli cells directs the gonad toward a male-specific fate. The cells in the early bipotential gonad undergo de novo organization to form testis cords that enclose germ cells inside tubules lined by epithelial Sertoli cells. Although Sertoli cells are a driving force in the de novo formation of testis cords, recent studies in mouse showed that reorganization of the vasculature and of interstitial cells also play critical roles in testis cord morphogenesis. However, the mechanism driving reorganization of the vasculature during fetal organogenesis remained unclear. Here we demonstrate that fetal macrophages are associated with nascent gonadal and mesonephric vasculature during the initial phases of testis morphogenesis. Macrophages mediate vascular reorganization and prune errant germ cells and somatic cells after testis architecture is established. We show that gonadal macrophages are derived from primitive yolk-sac hematopoietic progenitors and exhibit hallmarks of M2 activation status, suggestive of angiogenic and tissue remodeling functions. Depletion of macrophages resulted in impaired vascular reorganization and abnormal cord formation. These findings reveal a previously unappreciated role for macrophages in testis morphogenesis and suggest that macrophages are an intermediary between neovascularization and organ architecture during fetal organogenesis.