A perivascular niche for multipotent progenitors in the fetal testis

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.

Tcf21+mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration

“…Multiple interstitial cell (CD90/PDGFRA/CoupTFII/Nes) populations can re-enter the cell cycle upon EDS-induced Leydig cell death. This suggests that the interstitial compartment contains a reserve Leydig or a general somatic cell progenitor population that can be activated in response to damage (Chen et al, 1996;Chen et al, 2010;Davidoff et al, 2004;Ge et al, 2006;Jiang et al, 2014;Kilcoyne et al, 2014;Kumar and DeFalco, 2018;Landreh et al, 2013;Qin et al, 2008). However, whether the reported molecular markers are expressed universally by a single population of Leydig stem cells or by distinct cell populations that all have the ability to regenerate remains difficult to tease apart.…”

“…However, whether the reported molecular markers are expressed universally by a single population of Leydig stem cells or by distinct cell populations that all have the ability to regenerate remains difficult to tease apart. This is due to the difficulty of performing single-cell transplantation and reconstitution experiments in the testis and the lack of multiplexed molecular barcoding tools for lineage tracing (Kumar and DeFalco, 2018;Rotgers et al, 2018;Shima et al, 2018). It is also unclear if a common somatic progenitor could give rise to additional cell types that persists in the adult, and what the role of such stem/progenitors would be in the normal adult testis.…”

Gestational vinclozolin exposure suppresses fetal Leydig cell development in rats

“…Previous studies demonstrated that FLCs were developed from stem Leydig cells [8,24]. Stem Leydig cells in the fetal testis are spindle-shaped and express NR2F2, also called COUP-TFII [8,[24][25][26]. We used NR2F2 as the biomarker to identify the stem Leydig cell and SOX9 as the biomarker to draw a boundary for the seminiferous cord.…”

WOMEN IN REPRODUCTIVE SCIENCE: To be or not to be a testis

“…The vascular niche is also important for the regulation of the steroidogenic progenitors that give rise to Leydig cells (Tang et al 2008, Defalco et al 2013. These progenitors arise both from the CE and from specialized cells along the gonad-mesonephros border (Defalco et al 2011, Kumar & DeFalco 2018.…”