Suzuki Shinnosuke, McCarrey John R, Hermann Brian P
Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249, USA.
Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249, USA.
Cell Rep. 2021 Feb 16;34(7):108752. doi: 10.1016/j.celrep.2021.108752.
Spermatogonial stem cells (SSCs) sustain spermatogenesis by balancing self-renewal and initiation of differentiation to produce progenitor spermatogonia committed to forming sperm. To define the regulatory logic among SSCs and progenitors, we performed single-cell RNA velocity analyses and validated results in vivo. A predominant quiescent SSC population spawns a small subset of cell-cycle-activated SSCs via mitogen-activated protein kinase (MAPK)/AKT signaling. Activated SSCs form early progenitors and mTORC1 inhibition drives activated SSC accumulation consistent with blockade to progenitor formation. Mechanistically, mTORC1 inhibition suppresses transcription among spermatogonia and specifically alters expression of insulin growth factor (IGF) signaling in early progenitors. Tex14 testes lacking intercellular bridges do not accumulate activated SSCs following mTORC1 inhibition, indicating that steady-state mTORC1 signaling drives activated SSCs to produce progenitor clones. These results are consistent with a model of SSC self-renewal dependent on interconversion between activated and quiescent SSCs, and mTORC1-dependent initiation of differentiation from SSCs to progenitor clones.
精原干细胞（SSCs）通过平衡自我更新和启动分化来维持精子发生，从而产生致力于形成精子的祖细胞精原细胞。为了确定SSCs和祖细胞之间的调控逻辑，我们进行了单细胞RNA速度分析并在体内验证了结果。一个主要的静止SSC群体通过丝裂原活化蛋白激酶（MAPK）/AKT信号通路产生一小部分细胞周期激活的SSCs。活化的SSCs形成早期祖细胞，mTORC1抑制驱动活化的SSC积累，这与祖细胞形成受阻一致。从机制上讲，mTORC1抑制会抑制精原细胞中的转录，并特异性改变早期祖细胞中胰岛素生长因子（IGF）信号的表达。缺乏细胞间桥的Tex14睾丸在mTORC1抑制后不会积累活化的SSCs，这表明稳态mTORC1信号驱动活化的SSCs产生祖细胞克隆。这些结果与一个模型一致，即SSC自我更新依赖于活化和静止SSCs之间的相互转换，以及mTORC1依赖的从SSCs到祖细胞克隆的分化启动。
