A revised A_single model to explain stem cell dynamics in the mouse male germline

Spermatogonial stem cells (SSCs) and progenitor spermatogonia encompass the undifferentiated spermatogonial pool in mammalian testes. In rodents, this population is comprised of A_single, A_paired and chains of 4-16 A_aligned spermatogonia. Although traditional models propose that the entire A_single pool represents SSCs, and formation of an A_paired syncytium symbolizes irreversible entry to a progenitor state destined for differentiation; recent models have emerged that suggest that the A_single pool is heterogeneous, and A_paired/A_aligned can fragment to produce new SSCs. In this review, we explore evidence from the literature for these differing models representing SSC dynamics, including the traditional 'A_single' and more recently formed 'fragmentation' models. Further, based on findings using a fluorescent reporter transgene (eGfp) that reflects expression of the SSC-specific transcription factor 'inhibitor of DNA binding 4' (Id4), we propose a revised version of the traditional model in which SSCs are a subset of the A_single population; the ID4-eGFP bright cells (SSC_ultimate). From the SSC_ultimate pool, other A_single and A_paired cohorts arise that are ID4-eGFP dim. Although the SSC_ultimate possess a transcriptome profile that reflects a self-renewing state, the transcriptome of the ID4-eGFP dim population resembles that of cells in transition (SSCtransitory) to a progenitor state. Accordingly, at the next mitotic division, these SSC_transitory are likely to join the progenitor pool and have lost stem cell capacity. This model supports the concept of a linear relationship between spermatogonial chain length and propensity for differentiation, while leaving open the possibility that the SSC_transitory (some A_single and potentially some A_paired spermatogonia), may contribute to the self-renewing pool rather than transition to a progenitor state in response to perturbations of steady-state conditions.