Lymphatic blood filling in CLEC-2-deficient mouse models

C-type lectin-like receptor 2 (CLEC-2) is considered as a potential drug target in settings of wound healing, inflammation, and infection. A potential barrier to this is evidence that CLEC-2 and its ligand podoplanin play a critical role in preventing lymphatic vessel blood filling in mice throughout life. In this study, this aspect of CLEC-2/podoplanin function is investigated in more detail using new and established mouse models of CLEC-2 and podoplanin deficiency, and models of acute and chronic vascular remodeling. We report that CLEC-2 expression on platelets is not required to maintain a barrier between the blood and lymphatic systems in unchallenged mice, post-development. However, under certain conditions of chronic vascular remodeling, such as during tumorigenesis, deficiency in CLEC-2 can lead to lymphatic vessel blood filling. These data provide a new understanding of the function of CLEC-2 in adult mice and confirm the essential nature of CLEC-2-driven platelet activation in vascular developmental programs. This work expands our understanding of how lymphatic blood filling is prevented by CLEC-2-dependent platelet function and provides a context for the development of safe targeting strategies for CLEC-2 and podoplanin.

C型凝集素样受体2（C-type lectin-like receptor 2，CLEC-2）被认为是伤口愈合、炎症及感染场景中的潜在药物靶点。但现有研究证据显示，CLEC-2及其配体平足蛋白（podoplanin）在小鼠终生维持血液与淋巴系统间的屏障功能中发挥关键作用，这成为该靶点开发的潜在阻碍。本研究采用全新构建及已建立的CLEC-2与平足蛋白缺陷小鼠模型，以及急性、慢性血管重构模型，对CLEC-2/平足蛋白的这一功能特性展开了更为深入的探究。本研究发现，在发育成熟且未受外界干预的小鼠体内，血小板表面的CLEC-2表达并非维持血液与淋巴系统屏障功能的必需条件。但在慢性血管重构的特定情形下（如肿瘤发生过程中），CLEC-2缺陷可引发淋巴管血液充盈。本研究数据为成年小鼠体内CLEC-2的功能提供了全新认知，并证实了CLEC-2介导的血小板激活在血管发育程序中的核心必要性。本工作拓展了我们对CLEC-2依赖型血小板功能如何阻止淋巴管血液充盈的理解，同时为CLEC-2与平足蛋白的安全靶向治疗策略开发提供了重要依据。