Regulation of stem cell renewal and differentiation

Like all other renewing tissues, the seminiferous epithelium is able to react to cell loss and especially stem cell loss by mechanisms that initiate enhanced stem cell renewal to replace the lost cells. The potential of recovery of spermatogonial stem cells has been studied extensively at the cellular level by studying the reaction of the seminiferous epithelium to irradiation. In addition, data have become available on the genes involved in the regulation of spermatogonial stem cell renewal and differentiation.

6.1. Regulation at the Cellular Level

The seminiferous epithelium has several levels of response to cell loss or insufficient cell production, such as after irradiation or treatment with cyto-

Table 1

Ways the Seminiferous Epithelium Can Cope With Various Degrees of Cell Loss

Degree of cell loss Minor shortage in spermatogonia!

Greater than 50% loss of spermatogonia

Very severe (stem) cell loss

Epithelial reaction

Less density-related apoptosis of spermatogonia Enhanced proliferation of As, Apr, and

Aal spermatogonia Stem cells only self-renew during at least the first six divisions after cell loss static agents (Table 1). At the first level, small local shortages in cell numbers are abolished in a way made possible by the fact that the stem cell compartment generally produces too many differentiating cells. It has become clear that stem cell density varies considerably in different areas of seminiferous tubules; consequently, the number of differentiating cells produced also varies considerably (36,37). This varying density of the differentiating cells evens out by density-dependent apoptosis of spermatogonia. In high-density areas, many spermatogonia undergo apoptosis; only few or none do so in low-density areas (38). The result is an even distribution of spermatocytes over the seminiferous epithelium. At the same time, however, this density regulation mechanism serves as a mechanism to deal with relatively minor dips in local cell production and occasional cell loss. Second, although in the normal seminiferous epithelium stem cells and Apr and Aal spermatogonia only proliferate during a restricted part of the epithelial cycle, after cell loss the inhibition of the proliferative activity at the end of the proliferation period does not take place (39,40). Prolonged proliferation can then help enhance production of differentiating cells as well as stem cells.

In case of severe cell loss, there is a third level of response. It was found that, after a high dose of irradiation, surviving spermatogonial stem cells only self-renew during at least their first six divisions, leading to a rapid recovery of stem cell numbers in those areas where one or more stem cells did survive (41). Nothing is known yet about the triggers involved in preventing stem cell differentiation or enhancing self-renewal in such a situation.

6.2. Stem Cell Niches in the Seminiferous Epithelium

In several renewing tissues, stem cells were found to occupy specific areas. For example, in the intestine, stem cells reside near the bottom of the crypts (42), and stem cells in the bone marrow are supposed to occupy specific niches (43). Until very recently, in the seminiferous epithelium no such niches were found for spermatogonial stem cells. Now, it has become clear that most spermatogonial stem cells are present in those areas of seminiferous tubules that border interstitial tissue (10) (Fig. 4). Apparently, the interstitial tissue affects stem cell behavior. One could speculate that this is caused by the high testosterone levels present in these areas. In this respect, it is interesting that high testosterone levels have been found to prevent the differenti-ation of Aal spermatogonia into A1 spermatogonia (44-46). Possibly, testosterone also has a role in regulating stem cell behavior. However, it has to be kept in mind that germ cells do not possess androgen receptors, so tes-tosterone can only indirectly affect spermatogonia via peritubular myoid cells or (more likely) Sertoli cells, which both express this receptor.

6.3. Genes Involved in the Regulation of Stem Cell Behavior

Although from the above it is clear that the ratio between self-renewal and differentiation of spermatogonial stem cells is under the control of regulatory mechanisms, the genes involved in such mechanisms are largely unknown. However, recent data indicate that glial cell line derived neurotrophic factor (GDNF) is involved (Fig. 4). GDNF normally is secreted by Sertoli cells (47); a subset of spermatogonia, Ret and GDNF family receptor a-1 (GFR-a1), expresses the receptors for this growth factor (48). On ectopic expression of GDNF in spermatogonia, large clusters of single type A spermatogonia are formed, and normal spermatogenesis is suppressed. Moreover, in mice overexpressing GDNF in spermatogonia, seminomatous germ cell tumors are formed at about 1 yr of age (49). GDNF-deficient mice die during the first postnatal day (50), whereas the heterozygotes survive. In these mice, spermatogenesis deteriorates with age as spermatogonia are depleted (48). It was concluded that GDNF has a role in the regulation of self-renewal and differentiation of spermatogonial stem cells. Too high levels of GDNF prevent differentiation and cause accumulation of stem cells, and low levels favor differentiation over self-renewal and cause stem cell depletion.

Furthermore, very recent data indicate that, in the classical spontaneous mouse mutant luxoid, adult males exhibit a progressive loss of spermatogonial stem cells (51). Apparently, the as-yet-unknown gene involved in this mutation also has a role in the regulation of spermatogonial stem cell renewal and differentiation (Fig. 5).

Fig. 4. Testis section as in Fig. 1B. A dark line is drawn over those parts of the tubule membrance on which most stem cells are expected to be present.
Fig. 5. Molecular regulation of spermatogonial stem cell renewal and differentiation.

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