Cellular plasticity in the Drosophila spermatogonial stem cell niche

描述（由申请人提供）：干细胞通过不对称分裂再生组织，产生更多的干细胞（自我更新）以及分化子细胞。虽然分化通常被认为是不可逆的，但越来越多的证据表明，不可逆性的规则可以在损伤或细胞培养后被打破。分化细胞向分化程度较低的细胞类型的转化，或去分化，赋予某些生物体显著的再生特性。然而，尽管经过了几个世纪的研究，去分化还不能从分子上理解。我们使用果蝇精子发生作为模型干细胞系统，因为它与哺乳动物精子发生相似，但我们可以精确定位产生精子的精原干细胞并从基因上操纵它们的微环境（生态位）。在这个生态位中，精原干细胞中Janus激酶-信号转导和转录激活因子（Jak-STAT）信号通路的激活阻止了分化。然而，通过在体内操纵Jak-STAT信号，我们发现这一谱系具有惊人的可塑性；分化中的精原细胞可以逆转其路径并去分化为精原干细胞。由于去分化可能是许多干细胞系统的普遍特征，我们建议使用果蝇遗传学的强大工具来研究去分化。我们确定去分化是否用于替换在衰老过程中丢失的干细胞，它是否是精原细胞的专有属性，或者它是否也被激活以再生这个生态位中的体细胞干细胞。我们也追求我们的初步数据支持两种遗传方法来确定参与去分化的因素。总之，这项工作将开始揭示分化细胞可以被诱导逆转其路径并成为功能性干细胞的分子机制。这将推动再生医学领域的发展，并进一步加深我们对精子干细胞更新的理解，这是男性生殖的一个基本方面。

DESCRIPTION (provided by applicant): Stem cells regenerate tissue by dividing asymmetrically, producing more stem cells (self-renewal) as well as differentiating daughters. Although differentiation is usually considered irreversible, there is increasing evidence that the rules of irreversibility can be broken following injury or in cell culture. The conversion of a differentiated cell to a less differentiated cell type, or dedifferentiation, endows certain organisms with remarkable regenerative properties. Despite centuries of investigation, however, dedifferentiation is not understood molecularly. We use Drosophila spermatogenesis as a model stem cell system, since it parallels mammalian spermatogenesis, yet we can precisely locate the sperm-producing spermatogonial stem cells and manipulate their microenvironment (niche) genetically. In this niche, activation of the Janus kinase-Signal Transducer and Activator of Transcription (Jak-STAT) signaling pathway within spermatogonial stem cells prevents differentiation. However, by manipulating Jak-STAT signaling in vivo we have discovered a surprising degree of plasticity in this lineage; differentiating spermatogonia can reverse their path and dedifferentiate into spermatogonial stem cells. Since dedifferentiation may be a general feature of many stem cell systems, we propose to use the powerful tools of Drosophila genetics to study dedifferentiation. We determine if dedifferentiation serves to replace stem cells lost during aging and if it is an exclusive property of spermatogonia of if it is also activated to regenerate somatic stem cells within this niche. We also pursue our preliminary data supporting two genetic approaches to identify factors involved in dedifferentiation. Together, this work will begin to reveal the molecular mechanisms by which differentiating cells can be coaxed to reverse their path and become functional stem cells. This will advance the field of regenerative medicine and also further our understanding of spermatogonial stem cell renewal, a fundamental aspect of male reproduction.