Lymphatic blood filling in CLEC-2-deficient mouse models

Abstract

2020): Lymphatic blood filling in CLEC-2deficient mouse models, Platelets, Abstract 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.

CLEC-2 Prevents Accumulation and Retention of Inflammatory Macrophages During Murine Peritonitis

“…Wild type (WT) C57BL/6 mice (12-14 weeks; males and females) were purchased from Harlan Laboratories (Oxford, UK). Platelet-specific CLEC-2-deficient ( 26 ) (CLEC1b fl/fl GPIbCre), haematopoietic-specific podoplanin deficient ( 10 ) (PDPN fl/fl Vav-iCre) and LifeAct-GFP ( 27 ) mice were used. All experiments were performed in accordance with UK law (Animal Scientific Procedures Act 1986) with approval of the local ethics committee and UK Home Office approval under PPL P2E63AE7B, PP9677279 and P0E98D513 granted to the University of Birmingham.…”

Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues

“…In CLEC-2-deficient mice, lymphatic vessels were filled with blood, resulting in embryonic lethality ( 85 ). In the tumorigenesis model induced by intradermal injection of B16F10 melanoma cells, CLEC-2 deficiency was also associated with blood filling in lymphatic vessels ( 86 ). However, future studies are needed to evaluate the molecular mechanism, how platelet-resident CLEC-2 can regulate lymphatic vessel separation during tumorigenesis.…”

Platelets, thrombo-inflammation and cancer

“…В исследовании на мышиных моделях с дефицитом CLEC-2 лимфатические сосуды были заполнены кровью, что приводило к гибели эмбрионов [42]. В эксперименте введение Тромбоциты, тромбовоспаление и онкологический процесс клеток меланомы B16F10 при дефиците CLEC-2 также приводило к наполнению кровью лимфатических сосудов [43]. Необходимы дальнейшие исследования для выявления причин, которые дают возможность CLEC-2 тромбоцитам регулировать разделение лимфатических и кровеносных сосудов во время роста опухоли.…”