The life cycle of platelet granules The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Sharda, Anish, and Robert Flaumenhaft. 2018. “The life cycle of platelet granules.” F1000Research 7 (1): 236. doi:10.12688/f1000research.13283.1. http://dx.doi.org/10.12688/ f1000research.13283.1. Published Version doi:10.12688/f1000research.13283.1 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:35981871 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA F1000Research 2018, 7(F1000 Faculty Rev):236 Last updated: 28 FEB 2018 REVIEW The life cycle of platelet granules [version 1; referees: 2 approved] Anish Sharda, Robert Flaumenhaft Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA First published: 28 Feb 2018, 7(F1000 Faculty Rev):236 (doi: Open Peer Review v1 10.12688/f1000research.13283.1) Latest published: 28 Feb 2018, 7(F1000 Faculty Rev):236 (doi: 10.12688/f1000research.13283.1) Referee Status: Abstract Invited Referees Platelet granules are unique among secretory vesicles in both their content and 1 2 their life cycle. Platelets contain three major granule types—dense granules, α-granules, and lysosomes—although other granule types have been reported. version 1 Dense granules and α-granules are the most well-studied and the most published physiologically important. Platelet granules are formed in large, multilobulated 28 Feb 2018 cells, termed megakaryocytes, prior to transport into platelets. The biogenesis of dense granules and α-granules involves common but also distinct pathways. Both are formed from the trans-Golgi network and early endosomes and mature F1000 Faculty Reviews are commissioned in multivesicular bodies, but the formation of dense granules requires trafficking from members of the prestigious F1000 machinery different from that of α-granules. Following formation in the Faculty. In order to make these reviews as megakaryocyte body, both granule types are transported through and mature in comprehensive and accessible as possible, long proplatelet extensions prior to the release of nascent platelets into the bloodstream. Granules remain stored in circulating platelets until platelet peer review takes place before publication; the activation triggers the exocytosis of their contents. Soluble N referees are listed below, but their reports are -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, not formally published. located on both the granules and target membranes, provide the mechanical energy that enables membrane fusion during both granulogenesis and Michael Marks, Children’s Hospital of exocytosis. The function of these core fusion engines is controlled by SNARE 1 regulators, which direct the site, timing, and extent to which these SNAREs Philadelphia and University of interact and consequently the resulting membrane fusion. In this review, we Pennsylvania Perelman School of assess new developments in the study of platelet granules, from their Medicine, USA generation to their exocytosis. 2 Walter Kahr, University of Toronto, Canada The Hospital for Sick Children, Canada Discuss this article Comments (0) Page 1 of 12 F1000Research 2018, 7(F1000 Faculty Rev):236 Last updated: 28 FEB 2018 Corresponding author: Robert Flaumenhaft ([email protected]) Author roles: Sharda A: Conceptualization, Writing – Original Draft Preparation; Flaumenhaft R: Conceptualization, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests: No competing interests were disclosed. How to cite this article: Sharda A and Flaumenhaft R. The life cycle of platelet granules [version 1; referees: 2 approved] F1000Research 2018, 7(F1000 Faculty Rev):236 (doi: 10.12688/f1000research.13283.1) Copyright: © 2018 Sharda A and Flaumenhaft R. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Grant information: RF has received support from the National Heart, Lung and Blood Institute (R01 HL125275 and R35 HL135775). AS received support from the Hemostasis and Thrombosis Research Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. First published: 28 Feb 2018, 7(F1000 Faculty Rev):236 (doi: 10.12688/f1000research.13283.1) Page 2 of 12 F1000Research 2018, 7(F1000 Faculty Rev):236 Last updated: 28 FEB 2018 Introduction by using luciferase-based luminescence techniques, release Platelets are anucleate, discoid-shaped blood cells essential for of preloaded [3H] serotonin, or membrane expression of lyso- hemostasis, which serves to maintain the integrity of the vascu- some-associated membrane protein 2 (LAMP2) or CD63 by flow lature upon injury. The functional role of platelets has expanded cytometry6. in recent years to include processes such as inflammation, innate immunity, growth and development, angiogenesis, wound Other platelet granules have been described. Platelets contain healing, and cancer metastasis1. Platelet granule exocytosis is about 1–3 lysosomes per platelet and peroxisomes, the platelet- central to platelet function and participates in the full repertoire specific function of which remains unclear. Lysosomal exocy- of platelet activities. Platelets contain at least three major types tosis is typically evaluated by estimation of released lysosomal of granules—α-granules, dense granules, and lysosomes—which enzymes such as beta hexosaminidase. An electron-dense carry distinct cargos and vary in biogenesis, trafficking, and granule defined by the presence of Toll-like receptor 9 (TLR9) exocytosis. In addition, platelets have peroxisomes and recently and protein disulfide isomerase (PDI), termed the T granule, has described T granules. This review focuses on the biogenesis of also been described, although its existence remains controversial9. platelet α- and dense granules and mechanisms of their exocytosis. PDI and other platelet-borne thiol isomerases have been reported to be packaged within a non-granular compartment derived Platelet granules from the megakaryocyte endoplasmic reticulum (ER), which α-Granules are unique to platelets and are the most abundant of may be associated with the dense tubular system10,11. the platelet granules, numbering 50–80 per platelet2. These gran- ules measure 200–500 nm in diameter and account for about 10% Biogenesis of platelet granules of platelet volume. They contain mainly proteins, both membrane- Formation of platelet granules begins in megakaryocytes, but associated receptors (for example, αIIbβ3 and P-selectin) and maturation continues in circulating platelets12,13. Human platelet soluble cargo (for example, platelet factor 4 [PF4] and fibrinogen). granule deficiency syndromes, also referred to as storage pool Proteomic studies have identified more than 300 soluble proteins disorders, and their related murine models have been a major that are involved in a wide variety of functions, including hemos- source of study of platelet granulogenesis. Gray platelet syn- tasis (for example, von Willebrand factor [VWF] and factor V), drome (GPS), an α-granule deficiency disorder, and Hermansky– inflammation (for example, chemokines such as CXCL1 and Pudlak syndrome (HPS), a group of dense granule deficiency interleukin-8), and wound healing (for example, vascular endothe- syndromes, are two such examples. GPS platelets contain lial growth factor [VEGF] and fibroblast growth factor [FGF])3. normal dense granules, whereas HPS6 platelets contain normal The classic representation of α-granules as spherical organelles α-granules, which suggests that these granules have distinct with a peripheral limiting membrane, a dense nucleoid, and pathways of biogenesis7,14,15. In recent years, many inherited progressively lucent peripheral zones on transmission electron disorders due to defects in transcription factors such as microscopy is probably simplistic and may be in part a prepara- RUNX1, GATA1, FLl1, GFI1b, and ETV6 have been found to tion artifact. Electron tomography with three-dimensional recon- impact megakaryopoiesis and impair platelet production and struction of platelets is notable for a significant percentage of maturation16–21. Many of these disorders are associated with one tubular α-granules that generally lack VWF4. More recent work or more granule deficiency states and have helped elucidate the using transmission electron microscopy and freeze substitution role of these genes in platelet granulogenesis. dehydration of resting platelets shows that α-granules are ovoid with a generally homogeneous matrix and that tubes form from α-Granule biogenesis α-granules upon activation5. Thus, whether or not there exists α-Granule proteins derive from both synthetic and endocytic significant structural heterogeneity among α-granules remains to pathways22. Synthetic pathways traffic translated proteins from be completely resolved. α-Granule exocytosis is evaluated prima- ER to α-granules. The endocytic pathway enables megakaryocytes rily by plasma membrane expression of P-selectin (CD62P) by and mature