Lymphatic blood filling in CLEC-2-deficient mouse models

Elizabeth Haining; Kate Lowe; Surasak Wichaiyo; Raghu P Kataru; Zoltan Nagy; Dean Kavanagh; Sian Lax; Ying Di; Bernhard Nieswandt; Benoît Ho-Tin-Noé; Babak J Mehrara; Yotis Senis; Julie Rayes; Steve Watson

doi:10.1080/09537104.2020.1734784

Lymphatic blood filling in CLEC-2-deficient mouse models

Elizabeth Haining, Kate Lowe, Surasak Wichaiyo, Raghu P Kataru, Zoltan Nagy, Dean Kavanagh, Sian Lax, Ying Di, Bernhard Nieswandt, Benoît Ho-Tin-Noé, Babak J Mehrara, Yotis Senis, Julie Rayes, Steve Watson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	352-367
Number of pages	16
Journal	Platelets
Volume	32
Issue number	3
Early online date	4 Mar 2020
DOIs	https://doi.org/10.1080/09537104.2020.1734784
Publication status	Published - 3 Apr 2021

Bibliographical note

Funding
This work was funded by the Ministry of Sciences and Technology of Thailand and the British Heart Foundation [Grant RG/13/18/30563] and the British Heart Foundation Accelerator Award [AA/18/2/34218]. SPW is a BHF Chair [CH03/003].

Keywords

Blood-lymphatic separation
CLEC-2
platelets
podoplanin

ASJC Scopus subject areas

Hematology

Access to Document

10.1080/09537104.2020.1734784Licence: Creative Commons: Attribution (CC BY)

HainingE2020LymphaticFinal published version, 3.12 MBLicence: Creative Commons: Attribution (CC BY)

BHF Research Accelerator Award
Bicknell, R. (Co-Investigator), Watson, S. (Co-Investigator), Rainger, E. (Co-Investigator), Senis, Y. (Co-Investigator), Fabritz, L. (Co-Investigator) & Kirchhof, P. (Principal Investigator)
British Heart Foundation
1/04/19 → 30/09/24
Project: Research
The platelet ITAM receptors, CLEC-2 and GPVI, in development, maintenance and thromboinflammatory processes in the vasculature
Rainger, E. (Co-Investigator), Kirchhof, P. (Co-Investigator), Brill, A. (Co-Investigator) & Watson, S. (Principal Investigator)
British Heart Foundation
1/08/14 → 31/07/19
Project: Research

Cite this

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title = "Lymphatic blood filling in CLEC-2-deficient mouse models",

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.",

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author = "Elizabeth Haining and Kate Lowe and Surasak Wichaiyo and Kataru, {Raghu P} and Zoltan Nagy and Dean Kavanagh and Sian Lax and Ying Di and Bernhard Nieswandt and Beno{\^i}t Ho-Tin-No{\'e} and Mehrara, {Babak J} and Yotis Senis and Julie Rayes and Steve Watson",

note = "Funding This work was funded by the Ministry of Sciences and Technology of Thailand and the British Heart Foundation [Grant RG/13/18/30563] and the British Heart Foundation Accelerator Award [AA/18/2/34218]. SPW is a BHF Chair [CH03/003].",

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AU - Haining, Elizabeth

AU - Lowe, Kate

AU - Wichaiyo, Surasak

AU - Kataru, Raghu P

AU - Nagy, Zoltan

AU - Kavanagh, Dean

AU - Lax, Sian

AU - Di, Ying

AU - Nieswandt, Bernhard

AU - Ho-Tin-Noé, Benoît

AU - Mehrara, Babak J

AU - Senis, Yotis

AU - Rayes, Julie

AU - Watson, Steve

N1 - Funding This work was funded by the Ministry of Sciences and Technology of Thailand and the British Heart Foundation [Grant RG/13/18/30563] and the British Heart Foundation Accelerator Award [AA/18/2/34218]. SPW is a BHF Chair [CH03/003].

PY - 2021/4/3

Y1 - 2021/4/3

N2 - 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.

AB - 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.

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Lymphatic blood filling in CLEC-2-deficient mouse models

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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Projects

BHF Research Accelerator Award

The platelet ITAM receptors, CLEC-2 and GPVI, in development, maintenance and thromboinflammatory processes in the vasculature

Cite this