Mechanisms of alternative fate decision in mammalian spermatogonial stem cells

描述(申请人提供)：在大多数哺乳动物组织中，组织干细胞通过持续的自我更新和分化来维持体内平衡。尽管这种细胞命运的决定对组织的动态平衡很重要，但干细胞后代致力于自我更新或分化的一般规则在很大程度上是未知的。目前的大多数研究范式都假定环境因素决定了单个干细胞后代的命运。出乎意料的是，我们的初步数据和已发表的研究表明，啮齿动物精原干细胞(SSC)后代以恒定的概率以随机方式自主地诱导自我更新和分化，这种平衡可能受到外部提示的调节。这些发现指出了指导哺乳动物SSC自我更新和分化的新机制，这可能被证明与其他类型的干细胞相关。在这里，我们建议研究小鼠SSC随机命运选择的生理规律和分子组成。具体地说，我们将研究影响SSC后代命运选择的特定内部和外部因素的作用，并通过遗传筛选发现促进自我更新的新的SSC内在因素。这项研究的见解可能会为恢复生育和优化节育的新治疗干预措施提供基础。

DESCRIPTION (provided by applicant): In most mammalian tissues, homeostasis is maintained by tissue stem cells that function through continued self-renewal and differentiation. Despite the importance of this cell fate decision to tissue homeostasis, the general rules by which stem cell progeny commit to the paths of self- renewal or differentiation are largely unknown. Most current paradigms presume that environmental cues determine the fate of individual stem cell progeny. Unexpectedly, our preliminary data and published studies show that rodent spermatogonial stem cell (SSC) progeny autonomously elicit self-renewal and differentiation in a stochastic manner with constant probability, and that this balance may be regulated by extrinsic cues. These findings point to new mechanisms guiding mammalian SSC self-renewal and differentiation, which will likely prove relevant to other stem cell types. Here w propose to investigate the physiological regulation and the molecular components governing mouse SSC stochastic fate choice. Specifically, we will examine the role of specific internal and external factors that can influence fate choice of SSC progeny and identify novel SSC intrinsic factors that promote self-renewal through a genetic screen. Insights from this study may provide the basis for new therapeutic interventions that restore fertility and optimize birth control.