Transcriptional basis of embryonic macrophage development

摘要 近年来人们认识到，组织驻留巨噬细胞（TRM）有助于组织稳态。 例如，在大脑中，已经提出小胶质细胞处理细胞外蛋白质并限制细胞外蛋白质。 由蛋白质如β-淀粉样蛋白和Tau蛋白形成的斑块的形成。这样的组织驻留宏- 造血干细胞曾被认为是来源于单核细胞，而单核细胞是在成年人的造血过程中产生的。 骨髓然而，我们现在了解到，TRM是在胎儿期产生的，来自祖细胞 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体持续存在， 并且不能被来自成人骨髓的循环单核细胞有效地替代 和造血功能研究这种胚胎衍生的宏细胞功能的一个障碍是， 另一个问题是关于它们发育的信息相对缺乏，特别是转录前体， 指导他们发展的基因。缺乏这种信息会妨碍模型系统的设计， 这些细胞可以被阻止发育，这将允许它们在体内的功能被定义， 积极的方式。本申请旨在确定巨噬细胞胚胎发育的基础， es.它基于以下初步数据：1）鉴定了在确定性免疫应答中使用的Zeb2增强子（在~165kb处）， 造血支持来自成人骨髓的单核细胞/巨噬细胞发育; 2）表明， 这种增强子不是胚胎巨噬细胞发育中Zeb2表达所必需的，并且3）鉴定了两种 在胚胎卵黄囊和胎肝祖细胞中具有选择性活性的其它Zeb2增强子。 本申请将（目的1）测试这些胚胎活性Zeb2增强子在支持胚胎发育中的作用。 细胞巨噬细胞发育，并（目的2）确定其胚胎活动的转录基础。 Aim 1可直接建立胚胎巨噬细胞缺陷模型， 搜索与免疫细胞支持组织稳态相关的其他领域。除此之外，基本信息 关于原始和成人造血之间的相似性或差异可能有进一步的用途，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β-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.