Transcriptional basis of embryonic macrophage development

摘要 近年来，人们认识到组织驻留巨噬细胞(TRMS)有助于组织内环境的稳定。 例如，在大脑中，小胶质细胞被提出处理细胞外蛋白并限制 由-淀粉样蛋白和牛磺酸蛋白等蛋白质形成的斑块。这种驻留在组织中的宏模型 噬菌体曾经被认为是从单核细胞中产生的，而单核细胞出现在成人的最终造血过程中。 骨髓。然而，我们现在了解到，TRMS起源于胎儿时期，并起源于祖细胞。 在卵黄囊和胎儿肝脏中。在某些组织中，这些胚胎来源的巨噬细胞群持续存在。 在成人一生中，不能有效地被来自成人骨髓的循环单核细胞替代 和明确的造血功能。研究这种胚胎来源的巨噬细胞的功能的一个障碍是 噬菌体是关于其发育的相对缺乏的信息，特别是转录水平。 指导他们发展的克。缺乏这样的信息阻碍了模型系统的设计，其中 这些细胞可以被阻止发育，这将允许在体内定义它们的功能-- 完全正确的方式。目前的应用旨在确定巨细胞胚胎发育的基础-- 艾斯。它基于以下初步数据：1)确定了FINTIAL中使用的ZEB2增强子(-165kb) 支持成人骨髓单核/巨噬细胞发育的造血细胞；2)显示 该增强子不是ZEB2在胚胎巨噬细胞发育中表达所必需的，并且3)确定了两个 在胚胎卵黄囊和胎肝祖细胞中选择性活跃的其他ZEB2增强子。 该应用程序将(目标1)测试这些胚胎活性ZEB2增强剂在支持胚胎发育方面的作用。 ONIC巨噬细胞的发育，以及(目标2)确定其胚胎活动的转录基础。 AIM 1可直接制作胚胎巨噬细胞缺乏症模型，这将立即有利于恢复 寻找与免疫细胞支持组织动态平衡相关的其他领域。除此之外，基本信息 关于原始和成人造血之间的相似或不同之处可能有进一步的用途，例如在 增加了控制胎儿基因表达以弥补先天或后天缺陷的方法 在成人基因表达中，例如在-地中海贫血中。

ABSTRACT It has been appreciated recently that tissue-resident macrophages (TRMs) contribute to tissue homeostasis. For example, in the brain, microglia have been proposed to process extracellular proteins and to restrict the formation of plaque formed from proteins such as -amyloid and Tau proteins. Such tissue-resident macro- phages were once thought to be derived from monocytes that arise in definitive hematopoiesis in the adult bone marrow. However, we now understand that TRMs are derived during fetal life and arise from progenitors in the yolk sac and fetal liver. In some tissues, these embryonically derived macrophage populations persist throughout adult life and are not efficiently replaced by circulating monocytes arising from adult bone marrow and definitive hematopoiesis. One impediment to studying the functions of such embryonically derived macro- phages is the relative paucity of information regarding their development, specifically the transcriptional pro- grams that guide their development. The lack of such information prevents the design of model systems where these cells can be prevented from developing, which would allow their in vivo functions to be defined in a defin- itive way. The current application is aimed at defining the basis for the embryonic development of macrophag- es. It is based on preliminary data that has: 1) identified the Zeb2 enhancer (at -165kb) used in definitive hematopoiesis supporting monocyte/macrophage development from the adult bone marrow; 2) showed that this enhancer is not required for Zeb2 expression in embryonic macrophage development, and 3) identified two other Zeb2 enhancers that are selectively active in the embryonic yolk sac and fetal liver progenitors. This application will (Aim 1) test these embryonically active Zeb2 enhancers for their role in supporting embry- onic macrophage development, and (Aim 2) determine the transcriptional basis for their embryonic activity. Aim 1 may directly produce models of embryonic macrophage deficiency, which would immediately benefit re- search in other areas related to immune cell support of tissue homeostasis. Beyond this, the basic information on the similarities or differences between primitive and adult hematopoiesis could have further uses, such as in adding to ways in which fetal gene expression can be controlled to compensate for innate or acquired defects in adult gene expression, such as in -thalassemia.