Development of cmyb-independent macrophages from the primitive hematopoiesis

为了了解组织巨噬细胞在体内平衡和疾病中的作用，我们必须分析和确定这些重要免疫细胞的胚胎起源。最近，有报道称，在成人器官中，两个组织巨噬细胞亚群相邻存在，它们起源于原始和终代造血。虽然髓细胞从最终造血分化的必要因素是明确的，但对卵黄囊中引导原始髓细胞形成的因素知之甚少。在接下来的研究项目中，我想解决关于原始造血和cmyb非依赖性巨噬细胞起源的基本和关键问题。我想定义卵黄囊中原始造血所必需的外源性和内源性因素。诱导巨噬细胞所需的基质室的关键因素将首先被识别和表征。这将为卵黄囊中巨噬细胞发育的关键因素是否与胎儿肝脏或成人骨髓中的关键因素相同或不同提供证据。此外，对不依赖cmyb的组织巨噬细胞的不同髓系祖细胞的详细表征将确定在这些细胞上表达哪些特定的表面分子。有了这些数据，可能会发现一个谱系特异性标记物来识别、追踪和靶向cmyb非依赖性巨噬细胞。下一步，我想追踪组织巨噬细胞从卵黄囊的迁移路线并表征其分布，阐明胚胎发育过程中的定植顺序。最后，我想分析cmyb依赖性和cmyb非依赖性组织巨噬细胞在代谢综合征动物模型中稳态和炎症中的可能不同的功能。有了这些结果，我们将对cmyb非依赖性组织巨噬细胞的起源和功能有更深入的了解，从而更好地理解这些独特细胞在生理和病理生理环境中的作用。

In order to understand the role of tissue macrophages in homeostasis and disease, we have to analyze and identify the embryonic origin of these important immune cells. Recently, it was reported that two subpopulations of tissue macrophages, originating from primitive and definitive hematopoiesis, exist next to each other in adult organs. Whereas essential factors for the differentiation of myeloid cells from the definitive hematopoiesis are well defined, there is only scarce knowledge about factors guiding primitive myelopoiesis in the yolk sac.In the following research project I want to address basic and essential questions regarding the primitive hematopoiesis and the origin of cmyb-independent macrophages.I want to define exogenous and endogenous factors essential for the primitive hematopoiesis in the yolk sac. Key factors of the stromal compartment required for the induction of macrophages will be identified and characterized first. This will provide evidence whether the key factors for macrophage development in the yolk sac are identical or different to those in the fetal liver or in the adult bone marrow. Furthermore, a detailed characterization of the different myeloid progenitors of the cmyb independent tissue macrophages will define which specific surface molecules are expressed on these cells. With these data available a lineage specific marker might be identified to identify, trace and target cmyb-independent macrophages.In the next step I want to follow the migration routes and characterize the distribution of tissue macrophages from the yolk sac, clarifying the order of colonization during embryonic development. Finally I want to analyze the presumably different functions of cmyb-dependent and cmyb-independent tissue macrophages in homeostasis and inflammation in an animal model of metabolic syndrome. With these results available we will gain a deeper insight into the origin and function of cmyb-independent tissue macrophages, leading to a better understanding on the role of these unique cells in physiological and pathophysiological settings.