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Differentiation
Spermatogonial stem cells are the precursors to spermatozoa, which are produced through a series of differentiation steps. This is the alternative SSC outcome to self-renewal. SSCs survive within microenvironments, termed niches, which provide extrinsic stimuli that drive stem cell differentiation or self-renewal. The SSC niche is found in the seminiferous epithelium of mammalian testis, and is primarily constituted of Sertoli and peritubular myoid cells.

There are two primary differentiation stages, the first of which involves the transformation of As (single) spermatogonia into daughter progeny Apr (paired) spermatogonia, which are predestined to differentiate. These can divide further to create Aal (A-aligned) spermatogonia.

The second step involves the production of differentiating A1 spermatogonia from Apr or Aal spermatogonia. These A1 spermatogonia undergo a further five divisions to produce A2, A3, A4, intermediate and type B spermatogonia, which can enter meiosis I.

It takes around 64 days to produce mature spermatozoa from differentiating SSCs, and 100million spermatozoa can be produced each day.

Retinoic Acid
One of the major known substances driving the differentiation of SSCs, and therefore the production of spermatozoa, is Retinoic Acid (RA). There are theories supporting the hypotheses of both an indirect (via Sertoli cells) or a direct pathway.

It is thought that Sertoli cells produce RA through the conversion of circulating retinol to retinal and then finally to RA. Exposure to RA drives cellular differentiation into A1 spermatogonia and is implicated in further meiotic differentiation. As a result of differentiation, the genes required to maintain a SSC state are no longer expressed.