Adult Stem Cells in the Human Testis

Ellen Goossens, PhD, MSc; Herman Tournaye, MD, PhD, MSc

Disclosures

Semin Reprod Med. 2013;31(1):39-48. 

In This Article

Specialized Niches for Spermatogonial Stem Cells

Spermatogonial stem cells can develop in three different ways: They can renew themselves, they can differentiate, or they can go into apoptosis. The mechanism determining which pathway will be followed is the subject of a great deal of investigation. The discovery in 2000 of the stem cell niche in Drosophila has accelerated the study of this regulatory system.[49]

Niches are specialized microenvironments regulating tissue homeostasis by controlling stem cell self-renewal and differentiation. The SSC niche in the mammalian testis is located on the basal membrane of the seminiferous tubules and comprises Sertoli cells, peritubular myoid cells, and extracellular matrix components. Each niche houses one stem cell that is connected to the basement membrane through adhesion molecules (integrins). The fate of the stem cells is regulated by paracrine factors secreted by the niche. A key regulator of SSC self-renewal is glial cell line-derived neurotrophic factor (GDNF), which is secreted by Sertoli cells and acts on As, Apr, and Aal spermatogonia through the RET/GFRα1 receptor complex (Fig. 4).[34]

Figure 4.

The spermatogonial stem cell (SSC) niche. Under the stimulation of follicle-stimulating hormone (FSH), Sertoli cells secrete glial cell-derived neurotrophic factor (GDNF). GDNF binds to SSCs and induces self-renewal.

Sertoli cells are polarized columnar epithelial cells dividing the seminiferous tubule into a basal and an adlumenal compartment. The basal compartment comprises mainly spermatogonia, whereas the adlumenal compartment houses the more advanced germ cells. The two compartments are separated by tight junctions between Sertoli cells, the so-called blood-testis barrier (BTB). Germ cells have to cross the BTB during germ cell differentiation. The opening of the BTB regulates germ cell development by permitting the passage of preleptotene and leptotene spermatocytes. In this way, the differentiation process from leptotene spermatocytes up to mature sperm is separated from the systemic circulation. As such, Sertoli cells can supply developing germ cells with the necessary nutrients and establish an immune-privileged environment for haploid germ cells.[50]

Only recently, the influence of peritubular myoid cells on germ cell regulation was revealed. Because colony-stimulating factor 1 expression was detected in Leydig and peritubular myoid cells, and its receptor was highly enriched in THY1+ cells, a role on SSC maintenance was suggested.[51]

Not every germ cell located at the basal membrane is a SSC. Stem cell niches are not distributed randomly along the tubule but are thought to be localized in areas near the vasculature, implying a regulatory function for specific factors produced by the vascular endothelial cells.[52,53]

The cell density in the seminiferous tubules is kept constant by density-dependent degeneration of differentiating spermatogonia.[54] Because of these observations, it was suggested that there is no need for a precise regulatory mechanism to maintain the number of the stem cells in the normal testis. However, when the seminiferous epithelium is depleted by cytotoxic agents or irradiation, restoration of spermatogenesis must occur from stem cells. SSCs are less sensitive than differentiating spermatogonia but can still be lost. It was observed that, in this situation, the percentage of Apr daughter cells was much lower than in the normal testis, which indicates that stem cells prefer self-renewal to differentiation.[55,56]

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