Healthy Vasculature Crucial to Early-Stage Male Gonadal Development

Published October 2018 | Nature Communications

Male-specific development, from early fetal stages into adult life, depends on a complex process that leads to the formation of healthy Leydig cells. During fetal life, these cells help synthesize androgens required for initial virilization and patterning of the male external genitalia. In adulthood, these cells play vital roles in spermatogenesis and testosterone production.

When these cells malfunction, the results can include impaired spermatogenesis, low sperm count, ambiguous genitalia, and male infertility. Now research led by first author Deepti Kumar, PhD, and Tony De Falco, PhD, sheds new light on the crucial early steps of Leydig cell (LC) formation.

In studies of mouse models, the team traced LC formation to a perivascular niche microenvironment, where a population of Notch-active, nestin-positive progenitor cells give rise to Leydig cells, pericytes, and smooth muscle cells. This niche is located adjacent to the developing vasculature of the fetal testis.

This location proves to be important because the progenitor cells receive Notch signals from the vasculature that maintain a proper balance of cell types during cell differentiation. When blood vessel formation gets disrupted, Notch signaling fails and excessive LC differentiation occurs, which prematurely depletes the pool of progenitor cells and hinders formation of new LCs.

“This was surprising because no one had postulated that blood vessels would be a critical component of the niche for these progenitor cells,” De Falco says.

In other studies, vascular disruptions in the limbs and gut have been traced to fetal tissue structure anomalies. The new findings add sexual development to the growing list of conditions influenced by vascular development.

The next step, De Falco says, is to determine how this multipotent progenitor population progresses to a particular cell fate in the fetal testis.