Division of Germ Cell Biology, National Institute for Basic Biology, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan.
Mech Dev. 2012 Jan-Feb;128(11-12):610-24. doi: 10.1016/j.mod.2011.12.003. Epub 2011 Dec 20.
Homeostasis of tissues relies on the regulated differentiation of stem cells. In the epithelium of mouse seminiferous tubules, the differentiation process from undifferentiated spermatogonia (A(undiff)), which harbor the stem cell functions, to sperm occurs in a periodical manner, known as the "seminiferous epithelial cycle". To identify the mechanism underlying this periodic differentiation, we investigated the roles of Sertoli cells (the somatic supporting cells) and retinoic acid (RA) in the seminiferous epithelial cycle. Sertoli cells cyclically change their functions in a coordinated manner with germ cell differentiation and support the entire process of spermatogenesis. RA is known to play essential roles in this periodic differentiation, but its precise mode of action and its regulation remains largely obscure. We showed that an experimental increase in RA signaling was capable of both inducing A(undiff) differentiation and resetting the Sertoli cell cycle to the appropriate stage. However, these actions of exogenous RA signaling on A(undiff) and Sertoli cells were strongly interfered by the differentiating germ cells of intimate location. Based on the expression of RA metabolism-related genes among multiple cell types - including germ and Sertoli cells - and their regulation by RA signaling, we propose here that differentiating germ cells play a primary role in modulating the local RA metabolism, which results in the timed differentiation of A(undiff) and the appropriate cycling of Sertoli cells. Similar regulation by differentiating progeny through the modulation of local environment could also be involved in other stem cell systems.
组织的稳态依赖于干细胞的调节分化。在小鼠生精小管的上皮中，从具有干细胞功能的未分化精原细胞（A(undiff)）到精子的分化过程以周期性的方式发生，称为“生精上皮周期”。为了确定这种周期性分化的机制，我们研究了支持细胞（体细胞支持细胞）和视黄酸（RA）在生精上皮周期中的作用。支持细胞与生殖细胞分化协调周期性地改变其功能，并支持整个精子发生过程。已知 RA 在这个周期性的分化中起着至关重要的作用，但它的确切作用模式及其调控仍然很大程度上不清楚。我们表明，RA 信号的实验性增加既能诱导 A(undiff)分化，又能将支持细胞周期重置到适当的阶段。然而，外源性 RA 信号对 A(undiff)和支持细胞的这些作用受到紧密位置分化生殖细胞的强烈干扰。基于多种细胞类型（包括生殖细胞和支持细胞）中 RA 代谢相关基因的表达及其对 RA 信号的调控，我们在这里提出，分化的生殖细胞在调节局部 RA 代谢中起主要作用，从而导致 A(undiff)的定时分化和支持细胞的适当周期。通过调节局部环境，分化后代的类似调节也可能涉及其他干细胞系统。
