Bmi1 expression in long-term germ stem cells

Abstract

Asingle cells in undifferentiated spermatogonia are considered to be the most primitive forms of germ stem cells (GSCs). Although GFRα1 is thought to be a marker of Asingle cells, we found that Bmi1High is more specific than GFRα1 for Asingle cells. Bmi1High expression in Asingle cells is correlated with seminiferous stages, and its expression was followed by the proliferative stage of Asingle GSCs. In contrast, GFRα1 expression was seminiferous stage-independent. Fate analyses of EdU-positive Bmi1High-positive cell-derived Asingle cells revealed that these cells self-renewed or generated transient amplifying Apaired cells. Bmi1High-positive cells were resistant to irradiation-induced injury, after which they regenerated. Elimination of Bmi1High-positive cells from seminiferous tubules resulted in the appearance of tubules with seminiferous stage mismatches. Thus, in this study, we found that Bmi1High is a seminiferous stage-dependent marker for long-term GSCs and that Bmi1High-positive cells play important roles in maintaining GSCs and in regenerating spermatogenic progenitors after injury.

Paracrine Wnt/β-catenin signaling mediates proliferation of undifferentiated spermatogonia in the adult mouse testis

“…4C). These data are consistent with previous studies that showing that SSCs follow a neutral competition model (6,31,33,34), although additional, detailed analyses are needed to validate this model further.…”

“…4C). These results are consistent with a neutral competition model in which tissue stem cells are routinely lost and replaced in a stochastic manner, as previously demonstrated by the use of specific Cre lines of GFRα1, Ngn3, and Bmi1 in the testis (6,31,33,34).…”

Dynamic stem cell heterogeneity

“…Consistent with this model, post-transplantation colony formation and regeneration assays confirmed that the vast majority of stem cell activity is restricted to the population of undifferentiated (Kit-negative) spermatogonia (Shinohara et al, 2000). More recently, the identification of genetic markers that are enriched in or restricted to A s spermatogonia, including the transcriptional repressor ID4, the polycomb complex protein Bmi1 and the paired-box protein Pax7, allowed the potency of individual A s cells to be assessed (Aloisio et al, 2014;Komai et al, 2014;Oatley et al, 2011). These studies confirm that at least a fraction of A s cells retains long-term self-renewal potential, lending further support to the A s model paradigm.…”

ID4 levels dictate the stem cell state in mouse spermatogonia

“…This concept of a gradient of expression distinguishing SSC and progenitor populations is likely to be applicable to many molecules that have been considered SSC markers. In corroboration of this concept, a recent study utilized lineage tracing to show that SSCs are present in the BMI1 highly expressing population, whereas the population with lower expression is mostly progenitors (Komai et al, 2014).…”

“…Two major approaches for assigning stem cell function to specific populations are lineage tracing and transplantation. Although several cell populations, such as those marked by GFRA1 (Ebata et al, 2005;Grisanti et al, 2009;Hara et al, 2014), PAX7 (Aloisio et al, 2014), BMI1 (Komai et al, 2014) or NEUROG3 (Nakagawa et al, 2010) expression, have been identified as containing at least some SSCs using one of the approaches, the ID4 expressing population is the only one reported to date to be enriched for SSCs using both lineage tracing and transplantation (Chan et al, 2014;Sun et al, 2015). Moreover, in the current study we demonstrate through limiting dilution transplantation analysis that the ID4-EGFP Bright population is mostly, if not purely, SSCs.…”