Cellular plasticity in the Drosophila spermatogonial stem cell niche

描述(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)以及分化的子代。尽管分化通常被认为是不可逆转的，但越来越多的证据表明，在损伤后或在细胞培养中，不可逆转的规则可以被打破。分化的细胞转变为分化较少的细胞类型，或去分化，赋予某些生物显著的再生特性。同样，在一种称为转分化的过程中，一种类型的细胞通常可以被诱导采用新的命运，甚至是另一种血统的命运。然而，尽管经过几个世纪的研究，人们在分子水平上对脱分化和转分化知之甚少，特别是在发生在完整组织中的情况下。我们使用果蝇精子发生作为一个模型干细胞系统，因为它与哺乳动物的精子发生平行，但我们可以精确地定位产生精子的精原细胞(或生殖系干细胞，GSCs)，并从基因上操纵它们的微环境(生态位)。在这个利基中，局部细胞因子和转化生长因子-β信号促进干细胞更新，而离开利基的细胞分化。通过在体内操纵GSC的遗传维持，我们在这个谱系中发现了令人惊讶的可塑性；分化的精原细胞可以逆转它们的路径，并去分化为GSC。其他形式的损伤也会触发这种组织中干细胞再生的新机制。由于细胞命运转换(或可塑性)可能是许多干细胞系统的一个普遍特征，但在完整的组织中往往很难研究，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被诱使逆转其路径并成为具有功能的干细胞的分子机制。这将促进再生医学领域的发展，并加深我们对精原干细胞更新的理解，精原干细胞更新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.