Proliferation and differentiation of spermatogonial stem cells

Abstract

Spermatogonial stem cells (As spermatogonia) are single cells that either renew themselves or produce Apr (paired) spermatogonia predestined to differentiate. In turn, the Apr divide into chains of Aal (aligned) spermatogonia that also divide. The ratio between self-renewal and differentiation of the stem cells is regulated by glial cell line-derived neurotrophic factor produced by Sertoli cells, while the receptors are expressed in stem cells. As, Apr and Aal spermatogonia proliferate during part of the epithelial cycle forming many Aal spermatogonia. During epithelial stage VIII, almost all Aal spermatogonia, few Apr and very few As spermatogonia differentiate into A1 spermatogonia. A number of molecules are involved in this differentiation step including the stem cell factor-c-kit system, the Dazl RNA binding protein, cyclin D2 and retinoic acid. There is no fine regulation of the density of spermatogonial stem cells and consequently, in some areas, many A1 and, in other areas, few A1 spermatogonia are formed. An equal density of spermatocytes is then obtained by the apoptosis of A2, A3 or A4 spermatogonia to remove the surplus cells. The Bcl-2 family members Bax and Bcl-xL are involved in this density regulation. Several mechanisms are available to cope with major or minor shortages in germ cell production. After severe cell loss, stem cell renewal is preferred above differentiation and the period of proliferation of As, Apr and Aal spermatogonia is extended. Minor shortages are dealt with, at least in part, by less apoptosis among A2-A4 spermatogonia.