Spermatogonial stem cells in the human and other primates

7.1. Spermatogonia Cell Types in Primates

Spermatogonial multiplication and stem cell renewal in primates has been described in much less detail than in rodents. As in rodents, in primates there are A and B spermatogonia, but the composition of the type A sper-matogonial population is less clear. The A spermatogonia have been subdivided into Apale and Adark spermatogonia according to their staining with hematoxylin (52). The Apale spermatogonia divide once every cycle of the seminiferous epithelium. In the human, this means that they divide only once every 16 d (53,54). Adark spermatogonia in the normal situation are quiescent cells and are supposed to be reserve (stem) cells.

7.2. Nature of the Apale and Adark Spermatogonia

An important question is whether Apale and Adark are spermatogonial stem cells. To answer this question, an obvious approach is to look at the topographical arrangement of these spermatogonia on the basal membrane. In the normal seminiferous epithelium, the density of Apale and Adark sper-matogonia is relatively high. Therefore, the clones are too close together to decide whether Apale and Adark spermatogonia consist of clones of 1 or 2n cells comparable to spermatogonia in nonprimate mammals. However, such a clonal arrangement could be observed for both Apale and Adark spermatogonia during repopulation after irradiation, when spermatogonial density is much lower (55). In that situation, singles, pairs, and chains of Apale and Adark spermatogonia can be observed in tubule whole mounts. As it seems unlikely that the spermatogonial compartment would be principally different between primates and nonprimate mammals, it has been hypothesized that only the single cells among the Apale and Adark spermatogonia have stem cell properties (55,56).

7.3. Difference Between Apale and Adark Spermatogonia

Another question is what the principal difference, except for the difference in proliferative activity, between Apale and Adark spermatogonia is. It has generally been assumed that Adark spermatogonia are reserve (stem) cells. The first real evidence for such a reserve function came from a study in irradiated monkeys. In rhesus monkeys, shortly after irradiation, it was found that the number of Apale spermatogonia decreased to a minimum at about d 9 after irradiation; there was no change in the number of Adark spermatogonia (57). This pattern can be explained by the different proliferative activity of these cells. Irradiation kills the cells when they divide; conse quently, the proliferating Apale die, and the quiescent Adark survive. However, after longer intervals than 9 d, the Adark spermatogonia also decreased in number concomitant with a transient rise in the number of Apale. Finally, both cell types dropped to very low numbers. The transient nature of the increase in Apale after more than 9 d after irradiation can be explained by assuming that, after the decline in Apale numbers, the Adark spermatogo-nia are activated. The activation first causes the Adark to acquire the Apale appearance and accompanying proliferative activity. Then, having become Apale, they try to divide, but because of the lethal radiation damage acquired during the time they were Adark, proper division fails, and the cells enter apoptosis.

7.4. Conclusion

The Apale and Adark spermatogonia in primates are topographically arranged in singles, pairs, and chains of spermatogonia. Unless spermatogo-nial renewal and multiplication in primates is totally different from that in nonprimate mammals, only the singles among them are stem cells and are comparable to the As in nonprimates (Fig. 6). Only the Apale spermatogonia are able to proliferate and do so once every epithelial cycle. From this, it can be deduced that the formation of a chain of eight from a differentiating stem cell will take three cycles (i.e., 48 d in the human). The Adark spermatogonia are quiescent and only are activated after cell loss. When these cells are activated, they become Apale spermatogonia first and then start to proliferate. During repopulation by surviving stem cells, new Adark spermatogonia are set aside again (55). In comparing primate to nonprimate spermatogenesis, it is clear that there is much less proliferative activity of the stem cells in the primate seminiferous epithelium, even by the active stem cells, the Apale. A quiescent stem cell compartment, the Adark, is missing in nonprimate mammals. The low proliferative activity of spermatogonial stem cells in primates seems advantageous because this lowers the chance of errors in deoxyribo-nucleic acid (DNA) duplication during S phase. The less stem cells divide, the better (58).

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