Stem Cell Models Illustrate the Balance Between Self-renewal and Differentiation
SSC proliferation is slightly different for nonprimate and primate mammals. Because most research focuses on rodent spermatogenesis, both proliferation schemes are presented here.
Two models exist about stem cell renewal and spermatogonial multiplication in nonprimate mammals (the As model and the A0/A1 model), but the prevailing model is the As model, as proposed by Huckins and by Oakberg in 1971.[12,13] Spermatogenic proliferation/differentiation is accompanied by incomplete cell division, resulting in daughter cells that remain interconnected by intercellular bridges. The As or single, undifferentiated type A spermatogonia, is considered to be the most primitive cell or "true" spermatogonial stem cell. When As spermatogonia divide into two As cells, they usually migrate separately. If they remain connected to each other by cytoplasmic bridges, they are likely to be Apr. The production of type Apr spermatogonia is the first step toward differentiation. These interconnected spermatogonia gradually lose their stem cell potential (see later). Type Apr spermatogonia divide once more to produce groups of four type Aal spermatogonia, also connected to one another. The Aal cells proliferate resulting in chains of 8, 16, and occasionally 32 cells. Most of the Aal spermatogonia undergo a morphological change and transform into type A1 spermatogonia. These A1 spermatogonia are the first generation of differentiating A and B spermatogonia (Fig. 1).
Schematic representation of the As model for nonprimate spermatogonial differentiation. Black arrows indicate the direction of differentiation. The width of the white arrows reflects the relative probability of differentiation to A1 spermatogonia. (From Nakagawa T, Sharma M, Nabeshima Y, Braun RE, Yoshida S. Functional hierarchy and reversibility within the murine spermatogenic stem cell compartment. Science 2010;328:62–67. Used with permission.)
However, a revision of this As model might be necessary. Recently, several research groups found that the As population and spermatogonial chains of the same length are heterogeneous in respect to their gene expression[15–17] (Fig. 2).
Proposed spermatogonial subpopulations. Black arrows indicate the direction of differentiation of most of the cells. Dashed lines show the ways of "reversion." Arrows without asterisks were actually observed; those with asterisks were not observed but are proposed to occur with high probability. (From Nakagawa T, Sharma M, Nabeshima Y, Braun RE, Yoshida S. Functional hierarchy and reversibility within the murine spermatogenic stem cell compartment. Science 2010;328:62–67. Used with permission.)
Using the transplantation assay developed by the Brinster group,[18,19] it was possible to demonstrate that stem cell activity is limited to the undifferentiated spermatogonia As, Apr, and Aal.[20,21] Differentiating spermatogonia have a weaker potential to self-renew.
In primates, two morphologically different classes of type A spermatogonia are observed: the dark Ad (or "reserve" stem cells) and the pale Ap spermatogonia (or "renewing" stem cells). The self-renewal of the type Ap spermatogonia is analogous to that in the As model because most of the type Ap spermatogonia appear in clones of two, four, and eight cells, but single Ap cells also may exist. Furthermore, the Ad and Ap cells can transform into each other. Ad spermatogonia are often found in clusters. Such a cluster of Ad cells could be the result of a transformation of Ap into Ad at low renewal frequency. Conversely, after cytotoxic injury, the Ad may transform into Ap and start to proliferate. Spermatogenesis is initiated by two divisions of pairs or quadruplets of Ap cells: a first division, after which clones of Ap separate, and a second division, which leads to clones of B1 spermatogonia as well as pairs or quadruplets of Ap cells. These latter cells are responsible for the maintenance of the original size of the type A population. Because the Ap, which are found in clones of two or four cells, cycle continuously, the so-called true stem cells are probably the rarely dividing single Ap and Ad spermatogonia[25,26] (Fig. 3).
Semin Reprod Med. 2013;31(1):39-48. © 2013 Thieme Medical Publishers