Cellular plasticity in the Drosophila spermatogonial stem cell niche

果蝇精原干细胞生态位的细胞可塑性

• 批准号: 8060588
• 负责人: Erika L Matunis
• 金额: $ 25.97万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060588
• 关键词: Age; Aging; Back; Cell Culture Techniques; Cells; Collection; Data; Daughter; Dependence; Drosophila genus; Gametogenesis; Genes; Genetic; Genetic Screening; Germ Cells; Homeostasis; Injury; Investigation; Janus kinase; Life; Marble; Mitotic; Modeling; Molecular; Natural regeneration; Normal tissue morphology; Organism; Process; Property; Regenerative Medicine; Reproduction; Research Personnel; STAT protein; Signal Pathway; Signal Transduction; Somatic Cell; Source; Spermatogenesis; Spermatogonia; Stem cells; Supporting Cell; System; Testis; Tissues; Work; base; cell type; cellular imaging; in vivo; male; migration; prevent; programs; regenerative; research study; response to injury; self-renewal; sperm cell; stem cell division; stem cell niche; stem cell population; tool; transdifferentiation

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.

描述（由申请人提供）：干细胞通过不对称分裂来再生组织，产生更多的干细胞（自我更新）以及分化子细胞。尽管分化通常被认为是不可逆的，但越来越多的证据表明，在损伤或细胞培养中，不可逆规则可以被打破。分化细胞向分化程度较低的细胞类型的转化，或去分化，赋予某些生物体显着的再生特性。然而，尽管经过几个世纪的研究，去分化仍未从分子层面得到理解。我们使用果蝇精子发生作为干细胞系统模型，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通过遗传方式操纵它们的微环境（生态位）。在这个生态位中，精原干细胞内 Janus 激酶信号转导和转录激活因子 (Jak-STAT) 信号通路的激活可防止分化。然而，通过体内操纵 Jak-STAT 信号传导，我们发现该谱系具有令人惊讶的可塑性。分化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，因此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可以替代衰老过程中丢失的干细胞，以及它是否是精原细胞的专有特性，或者它是否也被激活以在这个生态位内再生体干细胞。我们还追求支持两种遗传方法的初步数据，以确定参与去分化的因素。总之，这项工作将开始揭示诱导分化细胞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原干细胞更新（男性生殖的一个基本方面）的理解。