Developmental kinetics and transcriptome dynamics of stem cell specification in the spermatogenic lineage

Abstract

Continuity, robustness, and regeneration of cell lineages relies on stem cell pools that are established during development. For the mammalian spermatogenic lineage, a foundational spermatogonial stem cell (SSC) pool arises from prospermatogonial precursors during neonatal life via mechanisms that remain undefined. Here, we mapped the kinetics of this process in vivo using a multi-transgenic reporter mouse model, in silico with single-cell RNA sequencing, and functionally with transplantation analyses to define the SSC trajectory from prospermatogonia. Outcomes revealed that a heterogeneous prospermatogonial population undergoes dynamic changes during late fetal and neonatal development. Differential transcriptome profiles predicted divergent developmental trajectories from fetal prospermatogonia to descendant postnatal spermatogonia. Furthermore, transplantation analyses demonstrated that a defined subset of fetal prospermatogonia is fated to function as SSCs. Collectively, these findings suggest that SSC fate is preprogrammed within a subset of fetal prospermatogonia prior to building of the foundational pool during early neonatal development.

DAZL mediates a broad translational program regulating expansion and differentiation of spermatogonial progenitors

“…Because we characterized translation and DAZL’s targets in undifferentiated spermatogonia from a synchronized first round of spermatogenesis, some of our results may represent the unique regulation that occurs within the first round, which originates from prospermatogonia, as opposed to later cycles of spermatogenesis, which arise from spermatogonial stem cells derived from prospermatogonia ( Hermann et al, 2015 ; Law et al, 2019 ; Yoshida et al, 2006 ). Our data may also reflect the larger spermatogonial stem cell pool that is established in the neonatal testis during synchronization ( Agrimson et al, 2017 ).…”

Reconstitution of prospermatogonial specification in vitro from human induced pluripotent stem cells

“…Due to the paucity of available data on perinatal human male germline development, the exact in vivo stage to which T1LCs correspond remains unclear. Recent studies have suggested that SSC activity, or the competency to produce self-sustaining spermatogenesis upon transplantation, has already been established, at least in part, in fetal prospermatogonia in mice 49 . It is therefore possible that T1LCs might be close to foundational SSCs, which upon transplantation, would be capable of regenerating complete spermatogenesis.…”

Unique Epigenetic Programming Distinguishes Regenerative Spermatogonial Stem Cells in the Developing Mouse Testis

“…In the postnatal mouse testis, prospermatogonia give rise to spermatogonia, exhausting the prospermatogonia population by postnatal day 5 (P5) ( Drumond et al., 2011 ; Kluin et al., 1982 ; Yoshida et al., 2006 ). By P6-8, distinct spermatogonial subtypes (SSC, progenitor, differentiating) can be distinguished on the basis of specific marker proteins ( Buaas et al., 2004 ; Chan et al., 2014 ; Valli et al., 2014 ), lineage tracing ( Hara et al., 2014 ; Sun et al., 2015 ), bulk ( Helsel et al., 2017 ), and single-cell (sc) ( Chen et al., 2018 ; Ernst et al., 2019 ; Green et al., 2018 ; Grive et al., 2019 ; Guo et al., 2018 ; Hermann et al., 2018 ; Jung et al., 2019 ; Law et al., 2019 ; Liao et al., 2019 ; Sohni et al., 2019 ; Velte et al., 2019 ) RNA-sequencing (RNA-seq), or transplantation analysis ( McLaren, 2003 ; Shinohara et al., 2000 ). SSCs retain regenerative capacity and divide to either self-renew or generate progenitors that lose regenerative capacity as they become primed to initiate spermatogenic differentiation giving rise to differentiating spermatogonia ( Drumond et al., 2011 ; Kluin et al., 1982 ; Yang et al., 2013 ).…”