Novel tissue injury regulation at an organ-organ junction

 描述(申请人提供)：在过去的15年里，组织修复研究人员发现了许多可以修复受损器官的干细胞。目前，人们对这些干细胞如何受到来自其他器官的信号的影响知之甚少。这种器官间的沟通在共用一个物理边界的器官损伤后尤其重要，其中修复组织必须与维持器官-器官边界的细胞特性相平衡。我们率先研究了一种简单的器官边界修复组织模型--果蝇中肠-后肠边界。在这样做的过程中，我们不仅发现了一种对器官-器官边界损伤做出反应的独特干细胞，而且还发现了分化(非干细胞)细胞在相同的组织修复过程中对倍性生长的作用。这两个协调的器官边界修复反应的生物学是这一提议的主题。我们将揭示组织修复的两个相对未被探索的方面的调节，与受伤的哺乳动物组织有有趣的相似之处。具体地说，损伤诱导的干细胞/细胞在人体器官边界的错误调节与胃肠道癌症有关。此外，分化的细胞通过倍性驱动的生长修复肝脏和其他几个器官。我们发现，在我们的系统中，损伤修复涉及：1)抑制分裂，有利于分化的器官边界细胞倍性/细胞大小的增加；2)在中肠-后肠交界处活跃分裂一个不同的干细胞。我们认为这两种机制在恢复失去的组织块的同时维持中肠-后肠的边界。使用我们的模型系统，我们可以针对后肠上皮的急性损伤。当我们这样做时，我们发现靠近中肠边缘的分化的成年后肠细胞不会分裂，而是增加细胞大小和基因组含量，这种保守的反应被称为肥大。在AIM1中，我们将确定为什么肥大是成人后肠的主要修复模式。为了回答这个问题，我们将确定成人后肠肥大修复和幼年后肠基于有丝分裂的修复之间的重要区别。在初步数据的基础上，我们将探索我们已经确定的特定信号通路和转录变化如何区分肥大反应和有丝分裂反应。在导致成人后肠肥大的相同损伤之后，我们发现细胞分裂也发生，但仅在特定群体的后肠相邻的中肠干细胞中发生。在AIM2中，我们将精确定义这些器官边界干细胞的分子调控/细胞输出。具体地说，我们将追踪这些独特的干细胞的谱系贡献，并确定我们已经确定的信号在器官间修复中的作用。我们还将研究器官边界损伤后发生的动态转录组变化的功能。鉴于很少有组织修复研究人员研究器官间的沟通或区分肥大和分裂之间的机制，我们的工作有望在理解组织修复策略方面取得重大的概念性进展。

 DESCRIPTION (provided by applicant): In the last 15 years, tissue repair researchers identified numerous stem cells that restore injured organs. Currently, little is known about how these stem cells are influenced by signals from other organs. This inter-organ communication is especially significant following injury of organs sharing a physical boundary, where repairing tissue must be balanced with maintaining cell identity at the organ-organ boundary. We pioneered study of a simple tissue model of organ boundary repair- the Drosophila midgut-hindgut boundary. In doing so, we not only uncovered a unique stem cell that responds to organ-organ boundary injury, but also discovered a role for ploidy growth by differentiated (non-stem) cells in the same tissue repair process. The biology of these two coordinated organ boundary repair responses is the subject of this proposal. We will reveal regulation of two relatively unexplored aspects of tissue repair with intriguing parallels to injured mammalian tissue. Specifically, injury-induced mis-regulation of stem cells/cell identity at a human organ boundary is linked to gastrointestinal cancer. In addition, differentiated cells repair the liver ad several other organs by ploidy-driven growth. We have found that injury repair in our system involves: 1) suppressed division in favor of ploidy/cell size increases in differentiated organ boundary cells and 2) active division of a distinct stem cell at the midgut- hindgut boundary. We argue these two mechanisms cooperate to restore lost tissue mass while maintaining the midgut-hindgut boundary. Using our model system, we can target acute injury to the hindgut epithelium. When we do this, we find differentiated adult hindgut cells near the midgut border do not divide but instead increase in cell size and genome content, a conserved response known as hypertrophy. In AIM1, we will determine why hypertrophy is the primary repair mode in the adult hindgut. To answer this question, we will identify important differences between hypertrophic repair in the adult hindgut and canonical mitosis-based repair in the juvenile hindgut. Expanding on preliminary data, we will explore how specific signaling pathways and transcriptional changes that we have identified distinguish between hypertrophic and mitotic responses. Following the same injury that induces adult hindgut hypertrophy, we find cell division also occurs, but only in a specific population of hindgut-adjacent midgut stem cells. In AIM2, we will precisely define the molecular regulation/cellular output of these organ boundary stem cells. Specifically, we will trace the lineage contribution of these distinctive stem cells an determine the role of signals we have identified in inter-organ repair. We also will examine the function of dynamic transcriptome changes that occur following organ boundary injury. Given that few tissue repair researchers study inter-organ communication or the mechanisms that discern between hypertrophy and division, our work promises significant conceptual advances in understanding tissue repair strategies.