Cellular plasticity and testis regeneration

摘要 许多成年组织通过干细胞的活性来替换由于正常磨损和撕裂而丢失的细胞， 但在受伤时可以使用完全不同的策略。理解和控制 再生，或响应于损伤而失去的组织或器官的再生长，是一个长期存在的问题。 生物学的目标具有在细胞生长抑制下采用其他细胞类型的生物学特性的能力的细胞。 特定条件或细胞可塑性是再生的关键因素。干细胞和 即使是分化的细胞也有惊人的可塑性，使它们能够适应新的环境。 修复和重建受损组织这是对微环境改变的反应， 在损伤后出现，但调节可塑性的机制知之甚少。现有 在资助期间，我们发现受损器官将非干细胞转化为干细胞进行修复， 组织。由于细胞可塑性是组织再生的一般特征，我们 使用两种方法确定体内调节成体体细胞再生的机制， 功能相似的系统：哺乳动物和果蝇的睾丸。在目标1中，我们建立在 发现果蝇睾丸中静止的体细胞转分化为干细胞 在损伤后，使用实时成像，谱系追踪和遗传操作来识别 调节基因我们还研究了再生的异常后果，异位干细胞 果蝇睾丸中的生态位形成，并从这种罕见的细胞中获得基因表达数据。 组织来拼凑控制这一过程的机制。在目标2中，我们扩展了新的 初步数据显示，成年小鼠睾丸的损害，在形式的消融Leydig 细胞，触发这些重要的静止类固醇生成细胞的再生。刻画了 细胞在细胞和分子水平上受损和老化时产生新的Leydig细胞。 这些目标将共同揭示调节静止丧失的分子线索， 在体内两种不同系统内诱导再生，提供了一种有效的手段， 确定维持损伤诱导的组织修复的机制。

Abstract Many adult tissues replace cells lost due to normal wear and tear via the activity of stem cells, but can use entirely different strategies when injury occurs. The ability to understand and control regeneration, or the regrowth of lost tissues or organs in response to injury, is a long-standing goal in biology. Cells with the capacity to adopt the biological properties of other cell types under specific conditions, or cellular plasticity, are key contributors to regeneration. Stem cells and even differentiated cells can have surprising degrees of plasticity, allowing them to adopt new fates and rebuild damaged tissues. This happens in response to altered microenvironments that arise upon injury, but the mechanisms that regulate plasticity are poorly understood. In the prior funding period, we showed that a damaged organ converts non-stem cells to stem cells to repair the tissue. Since cellular plasticity is emerging as a general feature of tissue regeneration, we identify mechanisms regulating the regeneration of adult somatic cells in vivo using two functionally similar systems: mammalian and Drosophila testes. In Aim 1 we build on our finding that quiescent somatic cells in the Drosophila testis transdifferentiate into stem cells upon damage, using live imaging, lineage tracing and genetic manipulation to identify the regulatory genes. We also study the aberrant consequence of regeneration, ectopic stem cell niche formation in Drosophila testes, and obtain gene expression data from rare cells in this tissue to piece together the mechanisms that control this process. In Aim 2 we extend our new preliminary data showing that damage to the adult mouse testis, in the form of ablation of Leydig cells, triggers regeneration of these important quiescent steroidogenic cells. We characterize cells giving rise to new Leydig cells upon damage and aging at the cellular and molecular level. Together these Aims will reveal the molecular cues regulating loss of quiescence and the induction of regeneration within two different systems in vivo, providing a potent means to determine the mechanisms sustaining damage-induced tissue repair.