Regulation of the proliferation of spermatogonial stem cells

Abstract

Summary The proliferating cells in the seminiferous epithelium can be subdivided into the (morphologically) undifferentiated and the differentiating spermatogonia. In turn the undifferentiated spermatogonia can be subdivided according to their topographical arrangement into clones consisting of one cell, the A-single (As) spermatogonia, two cells, the A-paired (Apr) spermatogonia or groups of 4, 8 or 16 cells, the A-aligned (Aal) spermatogonia. Most likely the As spermatogonia are the stem cells of spermatogenesis. When these cells divide their daughter cells can either migrate away from each other and become two new stem cells or stay together as Apr spermatogonia. The Apr spermatogonia can divide further to form Aal spermatogonia. Although suggestions have been made for the existence of a class of long-cycling stem cells with a higher probability for self-renewal, all cell kinetic data are still compatible with a homogeneous population of stem cells, the proliferative activity of which varies during the cycle of the seminiferous epithelium. Radiobiological studies have revealed that the radiosensitivity of the stem cells varies with their proliferative activity and that there is no particular class of radioresistant stem cells. In both rat and Chinese hamster the cell cycle time of the undifferentiated spermatogonia appeared to be much longer than that of the differentiating spermatogonia. All types of undifferentiated spermatogonia have the same minimum cell cycle time. However, the As spermatogonia, the stem cells, generally divide after longer intervals. The proliferative activity of the undifferentiated spermatogonia varies during the cycle of the seminiferous epithelium. At a certain moment during the epithelial cycle the undifferentiated spermatogonia, including the stem cells, are stimulated to proliferate. After a period of active proliferation the Apr and Aal spermatogonia are arrested in G1 phase possibly by the production of a chalone by the differentiating spermatogonia. In both rat and Chinese hamster the As spermatogonia are less sensitive towards this inhibition and continue to proliferate for some time longer. In the normal epithelium the probability of self-renewal of the stem cells varies with their proliferative activity in such a way that is low during active proliferation. In the normal epithelium there appeared to be no regulatory mechanism to ensure an even density of the stem cells. A large variation in stem cell density was found between areas. However, after heavy cell loss, for example after irradiation, the probability of self-renewal was found to be close to 100%. In primates the undifferentiated spermatogonia are composed of the so-called Ap and Ad spermatogonia. Studies after irradiation have revealed that these cells too, are composed of clones of 1, 2, 4, 8 or 16 cells. The Ad spermatogonia are quiescent in the normal epithelium but they were found to transform into active Ap spermatogonia after irradiation. Possibly the stimulation of the proliferative activity of the undifferentiated spermatogonia is very weak in primates, causing half of these cells to become arrested in G0 phase for long periods of time and to acquire the dark appearance after staining with haematoxylin.