Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα

Research output: Contribution to journalArticlepeer-review

Authors

  • Knut Falker
  • Maarten Criel
  • Madelene Lindkvist
  • Peter Pahlsson
  • Liza U Ljungberg
  • Mattias Tengdelius
  • Stephanie Watson
  • Johannes A Eble
  • Marc F Hoylaerts
  • Jonas Emsley
  • Peter Konradsson
  • Yi Sun
  • Magnus Grenegard

Colleges, School and Institutes

Abstract

Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)-dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)-like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.

Bibliographic note

Publisher Copyright: © 2019 by The American Society of Hematology Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

Details

Original languageEnglish
Pages (from-to)275-287
Number of pages13
JournalBlood Advances
Volume3
Issue number3
Early online date30 Jan 2019
Publication statusPublished - 12 Feb 2019

ASJC Scopus subject areas