Spatial, molecular and functional characterization of organ-specific lymphatic endothelial progenitor cells

器官特异性淋巴内皮祖细胞的空间、分子和功能特征

• 批准号: 377538279
• 负责人: Dr. Simon Stritt
• 金额: --
• 依托单位: Department for Immunology, Genetics and Pathology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/377538279?language=en
• 关键词: Spatial; molecular; functional; characterization; organ

The lymphatic vasculature controls fluid homeostasis, transport of lipids, antigens, and immune cells. Hence it plays central roles in lipid metabolism, tumor metastasis and immunity and consequently the lymphatic system is implicated in the pathogenesis of common diseases such as obesity, autoimmunity, atherosclerosis and cancer. Recently, novel, non-venous-derived lymphatic endothelial progenitor cells (LEPCs) that contribute to the formation of organ-specific lymphatic vasculatures, e.g. in the mesentery, have been identified. I hypothesize that the embryonic origin defines molecularly and functionally distinct LEC populations, and that defects in one of the LEPC populations may account for the organ-specific manifestation of lymphatic dysfunction in primary lymphedema.In the proposed project genetic lineage tracing using novel reporter strains, state of the art imaging, fluorescence-activated cell sorting and single cell sequencing will be applied to decipher the precise spatial origin, function as well as the molecular identity of mesenteric LEPCs. Comparison of the gene expression profiles of non-venous and venous-derived LEPCs and LECs may reveal LEPC-specific genes that potentially determine the distinct functions of the mesenteric lymphatic vasculature. The role of one or two in vitro validated signature genes in the formation and function of the mesenteric lymphatic vasculature will be investigated in vivo using transgenic mouse models. This work will identify the precise origin(s), translocation mechanisms as well as molecular and functional differences between organ-specific LEPCs. Together these results may uncover molecular and cellular mechanisms regulating and determining organ-specific lymphatic vessel development as well as function that could serve as basis for the development of novel therapeutic strategies for the treatment of diseases associated with lymphatic dysfunction.

淋巴管系统控制着体液的稳态，脂质、抗原和免疫细胞的运输。因此，它在脂质代谢、肿瘤转移和免疫中起着核心作用，因此淋巴系统与常见疾病如肥胖、自身免疫、动脉粥样硬化和癌症的发病机制有关。最近，新的，非静脉来源的淋巴管内皮祖细胞（LEPC），有助于器官特异性淋巴管的形成，例如在肠系膜，已被确定。我假设胚胎起源在分子和功能上定义了不同的LEC群体，并且其中一个LEPC群体中的缺陷可以解释原发性水肿中淋巴功能障碍的器官特异性表现。在所提出的项目中，使用新的报告菌株进行遗传谱系追踪，最先进的成像，荧光激活细胞分选和单细胞测序将被应用于破译精确的空间起源，功能以及肠系膜LEPC的分子特性。比较非静脉和静脉来源的LEPC和LEC的基因表达谱可能揭示LEPC特异性基因，这些基因可能决定肠系膜淋巴管系统的不同功能。将使用转基因小鼠模型在体内研究一个或两个体外验证的标签基因在肠系膜淋巴管系统的形成和功能中的作用。 这项工作将确定确切的起源（S），易位机制以及器官特异性LEPC之间的分子和功能差异。这些结果可能揭示调节和决定器官特异性淋巴管发育的分子和细胞机制以及功能，这些机制可以作为开发治疗淋巴功能障碍相关疾病的新治疗策略的基础。