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

Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):E2384-93. doi: 10.1073/pnas.1400057111. Epub 2014 May 27.

Abstract

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.

Keywords: VEGF; endothelial cell; mononuclear phagocyte; myeloid cell; sex determination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1
  • Cell Lineage
  • Fetus / blood supply
  • Fetus / cytology
  • Fetus / embryology
  • Flow Cytometry
  • 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
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / metabolism
  • Testis / blood supply*
  • Testis / cytology
  • Testis / embryology*
  • Time Factors
  • Yolk Sac / metabolism

Substances

  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Receptors, Chemokine
  • Green Fluorescent Proteins