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Reference Center for Platelet Disorders 33600 Pessac, France
Address all correspondence and requests for reprints to: Dr. Alan T. Nurden, Centre de Référence des Pathologies Plaquettaires, Plateforme Technologique d’Innovation Biomédicale, Hôpital Xavier Arnozan, 33600 Pessac, France. E-mail: Alan.Nurden{at}cnrshl.u-bordeaux2.fr.
Blood platelets are produced in large numbers from their parent cell, the megakaryocyte, which differentiates and matures in the bone marrow (1, 2). Anucleate platelets circulate for 7–10 d and mediate primary hemostasis. Platelets accumulate at injury sites in the vessel wall and, by a process of adhesion, activation, and aggregation, form a closely packed mass that constitutes the initial platelet plug, the first step in the arrest of bleeding. Platelets possess a series of surface membrane glycoproteins (GPs) that allow adhesion to exposed elements of subendothelial tissue—GPIb tethering to von Willebrand factor (VWF), and stable adhesion to collagen through the combined action of integrin 
2ß1 and the Ig family member GPVI. Activated, adherent platelets release serotonin that constricts small blood vessels. Cofactors such as secreted ADP and newly formed and released thromboxane A2 activate newly arriving platelets and accelerate hemostatic plug formation. Aggregation is mediated by the integrin IIbß3 that on activation binds fibrinogen and other adhesive proteins forming bridges between adjacent platelets (3, 4). Finally, platelets become procoagulant by 1) exposing anionic phosphatidylserine on their surface, and 2) receiving tissue factor-enriched microparticles from leukocytes by a P-selectin-dependent mechanism (5). In so doing, they form a catalytic surface permitting thrombin formation. The newly generated thrombin further stimulates platelet aggregation and transforms plasma fibrinogen into a fibrin network around the plug in which leukocytes and red cells become trapped. Platelets permit retraction and consolidation of what is now a blood clot. The importance of platelets is shown by the occurrence of lifelong bleeding syndromes when platelet adhesion or aggregation is congenitally defective (3). Although primary hemostasis is a vital physiological process, increasing evidence suggests that platelets also have a wider role in biology as regulators of tissue repair and tissue remodeling. The work of Fujiwara et al. (6) described in this issue extends the role of platelets to the regulation of neovascularization and granulosa cell luteinization during human corpus luteum remodeling.
The human corpus luteum is a unique endocrine organ that fills the postovulatory follicle during the menstrual cycle. Its role is to provide progesterone to the systemic circulation. Fujiwara et al. (6) used immunohistochemical procedures to show that considerable numbers of platelets and red cells were present at extravascular sites among luteinizing granulosa cells after ovulation. Increased vascular permeability beneath the follicular basement membrane may permit extravasation of blood cells into the spaces around luteinizing cells. The platelets, activated through adhesion to components of the extracellular matrix (collagen?), probably by the same mechanisms involved in hemostasis, expressed P-selectin demonstrating that platelet secretion had occurred. In vitro studies showed that progesterone production by luteinizing granulosa cells from patients undergoing in vitro fertilization therapy was promoted by direct contact with platelets during 4-d culture. In contrast, platelet-derived soluble factors induced both granulosa cell spreading and endothelial cell migration, evidence for multiple actions of platelets in the process of luteinization. An in vivo consequence is enhanced extracellular matrix formation around the luteal cells and the growth of vascular networks. It has been previously shown that luteinizing granulosa cells secrete proangiogenic factors such as vascular endothelial growth factor (VEGF) (7); although VEGF induces endothelial cell proliferation, it does not induce their migration. Interestingly, Fujiwara et al. (6) showed that when cocultured with platelets, granulosa cells inhibited endothelial cell migration. Although this could be interpreted as being contradictory to their hypothesis, the authors suggest a crucial regulatory role of granulosa cells in protecting against "overvascularization" and an excessive stimulatory effect of platelets. The role of platelets in these events was compared by the authors to their role and that of coagulation proteins in inflammation (8).
So, how does the platelet fulfill its new role? A cartoon of the structure of a resting platelet is shown in Fig. 1
. Although platelets are anucleate, they contain a large number of organelles including mitochondria, lysosomes, and the -granules and dense storage granules, the contents of which are secreted when platelets are activated. Dense granules contain serotonin, ADP, and ATP as major constituents. Recently, attention has focused on the -granules. Originally their contents were thought to be largely limited to adhesive proteins such as fibrinogen, VWF, fibronectin, vitronectin, and thrombospondin-1 (TSP-1; a protein virtually limited to platelets in blood) as well as some smaller basic proteins such as platelet factor 4 (PF4); in recent years, however, the number of proteins found to be stored in and released from platelets has exploded. Platelets contain secretable pools of both proangiogenic [e.g. VEGF, basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF)] and antiangiogenic factors (e.g. TSP-1, PF4, and endostatins) (9). An underlying factor promoting the widespread interest in these proteins was their potential role in the neovascularization of tumors and the possibility of using inhibitors of angiogenesis in anticancer therapy (9, 10). Many (but not all) platelet-stored proteins are listed in Fig. 1, including a whole variety of growth factors, chemokines, and cytokines. Proteins stored in -granules can either be synthesized and trafficked to their storage site in megakaryocytes (e.g. VWF, TSP-1, and PF4) or taken up by megakaryocytes or circulating platelets by endocytic and probably clathrin-dependent processes (e.g. fibrinogen, factor V) (11, 12, 13). The way that newly synthesized or endocytosed proteins are directed to -granules remains largely unknown. Also unknown is whether all -granules are alike, and a current hypothesis is that proangiogenic and antiangiogenic factors may be colocalized to different subpopulations of granules (14).
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-granule proteins that are involved: in liver regeneration platelet-derived serotonin mediates the repair process (21). Chemokines secreted from platelets such as RANTES have previously been reported to play a role in early pregnancy by inducing human extravillous trophoblast migration and differentiation (22). In the study by Fujiwara et al. (6), chemokines were released from platelets activated by extracellular matrices in the lumen of spiral arteries; the active agents responsible for human corpus luteum formation await identification but appear to involve both soluble secreted products and those that mediate cell-contact interactions. It should be noted that thrombin-activated platelets can also induce the autocrine production of growth factors from cells (23). In terms of vascularization, fibrin and activated platelets have been shown to cooperatively guide stem cells to sites of vascular injury and to promote differentiation toward an endothelial cell phenotype (24). Release of VEGF from platelets or stimulation of VEGF production from fibroblasts or other tissue cells by platelet-released TGF-ß1 may constitute a more direct way of stimulating vessel formation during luteinization.
In summary, there are now a variety of situations in which platelets have been shown to influence cell growth and cell differentiation. Platelets have a remarkable capacity to stimulate biological processes, although the net effect of platelet-released components may depend on both the site at which this is occurring and the number of platelets present. One promising outcome is the exploding therapeutic use of autologous platelet-rich plasma clots (16, 25). A major challenge to all investigators working in this field is to elucidate the precise pathways through which the platelet mediates its novel functions.
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Footnotes |
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Received April 19, 2007.
Accepted for publication May 2, 2007.
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References |
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 Top References |
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-granule targeting. J Throm Haemost 2:2231–2240[CrossRef]-granules of human megakaryocytes and platelets. J Clin Invest 84:1320–1324[Medline]
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