Abstract
Androgens responsible for male sexual differentiation in utero are produced by Leydig cells in the fetal testicular interstitium. Leydig cells rarely proliferate and, hence, rely on constant differentiation of interstitial progenitors to increase their number during fetal development. The cellular origins of fetal Leydig progenitors and how they are maintained remain largely unknown. Here we show that Notch-active, Nestin-positive perivascular cells in the fetal testis are a multipotent progenitor population, giving rise to Leydig cells, pericytes, and smooth muscle cells. When vasculature is disrupted, perivascular progenitor cells fail to be maintained and excessive Leydig cell differentiation occurs, demonstrating that blood vessels are a critical component of the niche that maintains interstitial progenitor cells. Additionally, our data strongly supports a model in which fetal Leydig cell differentiation occurs by at least two different means, with each having unique progenitor origins and distinct requirements for Notch signaling to maintain the progenitor population.
Highlights
Androgens responsible for male sexual differentiation in utero are produced by Leydig cells in the fetal testicular interstitium
While testis-specific vascular remodeling is important for establishing initial fetal testis cord architecture[22,23,24], it is not known whether vasculature is required for maintaining existing testis cord architecture or Sertoli cell differentiation, which could secondarily affect interstitial or Leydig cell differentiation
We demonstrate that vasculature is required for the initial formation, but not for the maintenance, of fetal testis cord architecture
Summary
Androgens responsible for male sexual differentiation in utero are produced by Leydig cells in the fetal testicular interstitium. 1234567890():,; Leydig cells (LCs) are steroidogenic cells present in the interstitial compartment of the testis They are responsible for the synthesis of androgens required for initial virilization and patterning of the male external genitalia during fetal life and proper male-specific development and spermatogenesis throughout postnatal and adult life. A recent single-cell RNA-seq study of Nr5a1-GFPpositive cells characterized the transcriptome of a putative interstitial progenitor population that gives rise to FLCs17, and a recent lineage tracing study of gonadal progenitor populations described an early WT1-positive progenitor at E10.5 which gives rise to Sertoli cells, fetal Leydig and interstitial cells, and ALCs18 Another important event in fetal testicular development is testis-specific vascular remodeling to generate a coelomic arterial network[19,20], which supplies oxygen and nutrients to the growing gonad and is a conduit for export of testosterone. Studies have shown that VEGF signaling drives testicular vascular development and organ patterning, as blocking VEGF signaling severely impaired malespecific coelomic vessel formation and endothelial migration without grossly affecting Sertoli cell or Leydig cell specification[22,24]
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