Open niche regulation of mouse spermatogenic stem cells

Abstract

In mammalian testes, robust stem cell functions ensure the continual production of sperm. In testicular seminiferous tubules, spermatogenic stem cells (SSCs) are highly motile and are interspersed between their differentiating progeny, while undergoing self‐renewal and differentiation. In such an “open niche” microenvironment, some SSCs proliferate, while others exit the stem cell compartment through differentiation; therefore, self‐renewal and differentiation are perfectly balanced at the population (or tissue) level, a dynamics termed “population asymmetry.” This is in stark contrast to the classical perception of tissue stem cells being cells that are clustered in a specialized “closed niche” region and that invariantly undergo asymmetric divisions. However, despite its importance, how the self‐renewal and differentiation of SSCs are balanced in an open niche environment is poorly understood. Recent studies have thrown light on the key mechanism that enables SSCs to follow heterogeneous fates, although they are equally exposed to signaling molecules controlling self‐renewal and differentiation. In particular, SSCs show heterogeneous susceptibilities to differentiation‐promoting signals such as Wnt and retinoic acid. Heterogeneous susceptibility to the ubiquitously distributed fate‐controlling extracellular signal might be a key generic mechanism for the heterogeneous fate of tissue stem cells in open niche microenvironments.

Retinoic acid signaling pathways

“…There are three classes of spermatogonia: stem (responsible for renewal), undifferentiated spermatogonia (termed 'A aligned ', which expand the pool of progenitors), and differentiating spermatogonia (including 'A1', which are committed towards spermatogenesis). RA is required early for differentiation of A aligned spermatogonia into A1 spermatogonia (A aligned -to-A1 transition) and then later for mature spermatid release (reviewed by de Rooij, 2001) (Hogarth and Griswold, 2010;Mark et al, 2015;Busada and Geyer, 2016;Yoshida, 2018). Expression pattern analyses have revealed that multiple cell types within the testis are involved in setting up and transducing the RA signal (reviewed by Hogarth and Griswold, 2010).…”

Competition for Mitogens Regulates Spermatogenic Stem Cell Homeostasis in an Open Niche

“…Traditionally, efforts to resolve the factors that control fate asymmetry place emphasis on short-range mitogenic and anti-differentiation signals from a definitive anatomical niche, a specialized microenvironment to which stem cells anchor, becoming physically separated from their differentiating progeny (Morrison and Spradling, 2008, Stine and Matunis, 2013, Watt and Hogan, 2000). However, in some tissues, such as mammalian blood and spermatogenesis, stem cell maintenance is thought to take place in a “facultative,” or “open,” niche (Morrison and Spradling, 2008, Stine and Matunis, 2013, Yoshida, 2018a), where stem cells are often highly motile and lie dispersed among their differentiating progeny. The question of how stem cell number is regulated in such environments is poorly understood.…”

“…In the definitive, or closed, niche environment of Drosophila and C. elegans gonads, self-renewal-promoting signals show a restricted distribution (Spradling et al., 2011). In mouse seminiferous tubules, factors known to regulate stem cell behavior (i.e., self-renewal-promoting glial cell line-derived neurotrophic factor [GDNF], the GFRα1 ligand [Chen et al., 2016, Meng et al., 2000], and differentiation-promoting retinoic acid [RA] and Wnt) are distributed in a spatially uniform manner around the tubule, while showing periodic temporal variation in concert with the seminiferous epithelial cycle (Sato et al., 2011, Sharma and Braun, 2018, Takase and Nusse, 2016, Tokue et al., 2017, Vernet et al., 2006, Ikami et al., 2015, Oakberg, 1956, Yoshida, 2018a). However, GFRα1 + cells show biased localization toward the vasculature (arterioles and venules) and surrounding interstitium; yet the basis of this localization is unknown (Chiarini-Garcia et al., 2001, Hara et al., 2014, Yoshida et al., 2007).…”

Mammalian germ cell migration during development, growth, and homeostasis

“…During the reproductive period, mammalian sperm production is supported by spermatogenic stem cells that achieve a balance between self‐maintenance and differentiation into spermatozoa . A transplantation assay suggested that spermatogenic stem cell function resides within the undifferentiated spermatogonia, which contain singly isolated cells (called A single ) and syncytia .…”