Fig. 1. Factors influencing the reprogramming of unipotent SSCs into pluripotent stem cells. Nanos2 is expressed preferentially in As and Apr undifferentiated spermatogonia and positively regulates Plzf and GFRα1 when overexpressed. GDNF, an essential extrinsic growth factor, plays critical roles in self-renewal of SSCs through its cognate receptor GFRα1. It appears that SSCs maintenance by Plzf is independent of the GDNF-GFRα1 signaling pathway. Although Oct4 and Sox2 are expressed transcriptionally in SSCs, their gene expression levels are significantly lower than in ES cells. This may explain the absence of another pluripotency marker, Nanog, which is upregulated by OCT4 and SOX2. Currently, p53 is the only known gene that negatively affects the reprogramming efficiency of SSCs. Tumor suppressors and cell cycle regulators may play a similar role in the reprogramming process. MiR-470 represses Oct4 expression by targeting the coding sequences upon ES cell differentiation. The seeding density, the culture time, and medium composition are factors that influence the reversion of the cellular state of SSCs. The absence of Nanog expression may explain the unipotency of SSCs. The testicular germ cell tumor-associated microRNAs, miR-372 and miR-373, mediate a complex process involved in the establishment of the pluripotent state in the absence of p53.
