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）以及分化的子细胞。虽然分化通常被认为是不可逆的，但越来越多的证据表明，不可逆的规则可以在损伤后或细胞培养中被打破。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。同样，在一个称为转分化的过程中，一种类型的细胞通常可以被诱导接受新的命运，甚至是另一种谱系的命运。然而，尽管进行了几个世纪的研究，但在分子水平上对去分化和转分化的了解很少，特别是在它们发生在完整组织中的情况下。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细胞（或生殖系干细胞，GSC）并从遗传学上操纵它们的微环境（生态位）。在这个小生境中，局部细胞因子和TGF-β信号传导促进干细胞更新，而离开小生境的细胞分化。通过在体内遗传操纵GSC维持，我们发现了该谱系中令人惊讶的可塑性程度;分化的精原细胞可以逆转其路径并去分化为GSC。其他形式的损伤也会触发该组织中干细胞再生的新机制。由于细胞命运的转变（或可塑性）可能是许多干细胞系统的一般特征，但往往难以在完整的组织中进行研究，我们建议使用果蝇遗传学的强大工具来研究这些事件。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，也将进一步加深我们对精原干细胞更新的理解，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. Similarly, cells of one type can often be induced to adopt a new fate even that of another lineage, in a process called transdifferentiation. Despite centuries of investigation, however, dedifferentiation and transdifferentiation are poorly understood at the molecular level, particularly in situations where they occur in intact tissues. We use Drosophila spermatogenesis as a model stem cell system, since it parallels mammalian spermatogenesis, yet we can precisely locate the sperm-producing spermatogonial (or germ line stem cells, GSCs) and manipulate their microenvironment (niche) genetically. In this niche, local cytokine and TGF-beta signaling promotes stem cell renewal, while cells leaving the niche differentiate. By manipulating GSC maintenance genetically in vivo we have discovered a surprising degree of plasticity in this lineage; differentiating spermatogonia can reverse their path and dedifferentiate into GSCs. Additional forms of damage also trigger novel mechanisms of stem cell regeneration in this tissue. Since cell fate transformation (or plasticity) may be a general feature of many stem cell systems, but is often difficult to study in intact tissues, we propose to use the powerful tools of Drosophila genetics to study these events. 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.