Developmental pathways regulating adult lung quiescence

 描述（由申请人提供）：组织以不同的方式对损伤做出反应，以修复和再生丢失的细胞和受损的结构。肺通过空间受限的干/祖细胞群的激活和通过干/祖细胞群的再进入对损伤做出强烈的反应。 将细胞分化成细胞周期。这种对损伤的强烈反应与正常的稳态形成鲜明对比，正常的稳态非常安静。一个学派认为，静止是许多组织中的默认状态，这是由于缺乏生长刺激，如培养条件所示。然而，这并不能完全解释细胞在组织稳态期间如何在体内复杂的微环境中保持静止。另一种假设是，静止是通过迄今未知的分子途径积极维持的。这种主动过程对于在正常稳态期间维持组织完整性所需的细胞静止与损伤后的快速再生反应之间的微妙平衡将是重要的。这些信息是重要的，因为这种状态下的破坏可能导致细胞增殖以不受控制的方式重新激活，并可能导致包括肺纤维化和癌症在内的几种肺部疾病。Hedgehog（Hh）通路是一种标志性信号传导通路，其通过平滑（Smo）介导的下游信号传导事件的旁分泌激活来协调包括肺在内的多个器官发育期间的上皮-间充质相互作用。在三种已知的Hh配体中，音刺猬（Shh）是最好理解的，在肺发育过程中高度表达，并在肺形态发生中起重要作用。尽管其在器官发育中的作用明确，但关于Hh信号传导是否或如何协调成人肺中的上皮-间充质相互作用以维持组织稳态或调节损伤和再生却知之甚少。通过下游效应物Gli 1的表达，Hh信号传导活性已在成人肺中被注意到，沿着的研究表明hedgehog促进体外间充质增殖。然而，Hh在正常成人组织静止中的功能或其在肺损伤和再生中的作用尚未在体内模型中研究。我们的初步数据表明，Hh信号在成人肺中是活跃的，并用于维持正常稳态期间以及近端气道损伤后的间充质静止。因此，Hh信号传导在肺静止中起关键作用，并且在肺对损伤的响应中是重要的。

 DESCRIPTION (provided by applicant): Tissues respond in different ways to injury to repair and regenerate lost cells and damaged architecture. The lung responds robustly to injury through activation of spatially restricted stem/progenitor cell populations and through re-entry of differentiated cells into the cell cycle. This robust response to injury stands in contrast to the normal homeostatic state, which is remarkably quiescent. One school of thought suggests that quiescence is a default state in many tissues resulting from lack of growth stimuli as demonstrated in culture conditions. However, this does not fully explain how cells remain quiescent within a complex microenvironment in vivo during tissue homeostasis. An alternative hypothesis is that quiescence is actively maintained through as yet unknown molecular pathways. Such an active process would be important for the delicate balance between cellular quiescence required for maintaining tissue integrity during normal homeostasis and the rapid regenerative response after injury. Such information is important given that disruption in this state could lead to re-activation of cell proliferation in an uncontrolled manner and may underlie several lung diseases including pulmonary fibrosis and cancer. The Hedgehog (Hh) pathway is a hallmark signaling pathway that coordinates epithelial-mesenchymal interactions during development in multiple organs including the lung, through paracrine activation of smoothened (Smo)-mediated downstream signaling events. Of the three known Hh ligands, sonic hedgehog (Shh) is the best understood, is highly expressed during lung development, and plays an essential role in lung morphogenesis. Despite its clear role in organ development, little is known about whether or how Hh signaling coordinates epithelial-mesenchymal interactions in the adult lung to maintain tissue homeostasis or modulate injury and regeneration. Hh signaling activity has been noted in the adult lung through expression of the downstream effector Gli1, along with studies suggesting hedgehog promotes mesenchymal proliferation in vitro. However, Hh's function in normal adult tissue quiescence or its role in injury and regeneration in the lung has not been examined in in vivo models. Our preliminary data suggest that Hh signaling is active in the adult lung and is used to maintain mesenchymal quiescence during normal homeostasis as well as after injury in the proximal airways. Thus, Hh signaling plays a critical role in maintainig lung quiescence and is important in the response of the lung to injury.