Spermatogenesis is a complex process by which the male germ-line stem cells (spermatogonial stem cells) self-renew and differentiate to produce sperm. Spermatogonial stem cells (SSCs) constitute one of the most important stem cell systems in the body, not only because they produce sperm which transmit genetic information across the generations, but because it has recently beendemonstrated that SSCs from mouse and human testis can convert to embryonic stem-like (ES-like) cells thus acquiring pluripotency (Kanatsu-Shinohara et al., 2004a; Guan et al., 2006; Seandel et al., 2007; Conrad et al., 2008; Kanatsu-Shinohara et al., 2008;Kossack et al., 2008). Within the microenvironment (the niche) of the seminiferous tubules, SSCs can be directed to one of two cell fate decisions:they self-renew to produce new stem cells in order to maintain the stem cell pool or differentiate into more advanced germ cells. When removed from their niche, SSCs can be reprogrammed biochemically to pluripotency. In physiological conditions, the SSCs self-renew slowly, however, they can divide rapidly in response to damage such as chemicals or radiation (Dym and Clermont, 1970; Meistrich,1986; Dym, 1994; de Rooij and Russell, 2000). The fate decisions of SSCs are mainly regulated by paracrine and potential autocrine molecules, which are produced by somatic cells and germ cells, respectively. A thorough understanding of the molecular mechanisms, particularly the signaling molecules and pathways, regulating self-renewal, differentiation, and the conversion of SSCs to pluripotent ES-likecells is essential for the regulation of spermatogenesis and has important implications in offering new therapeutic targets for male infertility and testicular cancers as well as for the conversion of SSCs to ES-like cells for patient-specific therapy.
This review mainly focuses on the key signaling molecules and pathways regulating self-renewal and differentiation of SSCs based on the work ofour group and others. Aberrant expression of the signaling molecules and the intracellular signaling pathways may lead to male infertility and testicular cancer. As a result, the signaling molecules and cascades now known or yet to be identified would become novel attractive targets for male contraception as well as for the treatment of male infertility and testicular cancer. Also we present anoverview of the unique characteristics and the potential of SSCs and underscore the important questions awaiting investigation in studies on signaling pathways regulating SSC fate decisions.
1. Morphological features, phenotypic characteristics, and potential of SSCs
The term “stem cell” was first introduced more than one century ago in the context of self-renewal to describe spermatogonia in thetestis (Regaud, 1901), but the origin of the term “stem cell” may be tracked to 1868 to an eminent German biologist Ernst Haeckel who used “stammzelle” (stem cell in German) to describe the ancestor unicellular organism [referenced in (Ramalho-Santos and Willenbring, 2007)]. Stem cells, by definition, are primitive cells that have the capacity to both self-renew and differentiate into one or morecell lineages (Weissman, 2000). There are two main types of stem cells, namely embryonic stem (ES) cells and adult stem cells. While ES cells derived from the inner cell mass of a blastocyst are capable of producing all the cell types in the body, the availability of these stem cells is limited due to ethical issues. Adult stem cells reside in various tissues and they can self-renew to maintain thepool of stem cells and differentiate into mature cells with particular functions. One of the advantages of using adult stem cells is that there are no ethical issues compared to using ES cells, and most importantly, several adult stem cells also demonstrate multipotency or pluripotency and are able to differentiate into a variety of cells that potentially can be used for regenerative medicine,...