Programmed Anuclear Cell Death Delimits Platelet Life Span

Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
Cell (Impact Factor: 32.24). 04/2007; 128(6):1173-86. DOI: 10.1016/j.cell.2007.01.037
Source: PubMed


Platelets are anuclear cytoplasmic fragments essential for blood clotting and wound healing. Despite much speculation, the factors determining their life span in the circulation are unknown. We show here that an intrinsic program for apoptosis controls platelet survival and dictates their life span. Pro-survival Bcl-x(L) constrains the pro-apoptotic activity of Bak to maintain platelet survival, but as Bcl-x(L) degrades, aged platelets are primed for cell death. Genetic ablation or pharmacological inactivation of Bcl-x(L) reduces platelet half-life and causes thrombocytopenia in a dose-dependent manner. Deletion of Bak corrects these defects, and platelets from Bak-deficient mice live longer than normal. Thus, platelets are, by default, genetically programmed to die by apoptosis. The antagonistic balance between Bcl-x(L) and Bak constitutes a molecular clock that determines platelet life span: this represents an important paradigm for cellular homeostasis, and has profound implications for the diagnosis and treatment of disorders that affect platelet number and function.

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    • "A. Sorolla et al. / Genomics xxx (2014) xxx–xxx Please cite this article as: A. Sorolla, et al., Genomics (2014), deacetylase (Hdac1) and Smchd1, a gene known to be involved in X chromosome inactivation [6]. ENU mutagenesis screens in mice have been useful for the study of a large number of physiological processes including haematopoiesis [26] [27] [28]. In most cases the mutations responsible for a phenotype have been loss of function mutations which read out as dominant (or gene dosage-dependent loss of function) mutations. "
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    ABSTRACT: Position-effect variegation of transgene expression is sensitive to the chromatin state. We previously reported a forward genetic screen in mice carrying a variegated α-globin GFP transgene to find novel genes encoding epigenetic regulators. We named the phenovariant strains “Mommes” for modifiers of murine metastable epialleles. Here we report positional cloning of mutations in two Momme strains which result in suppression of variegation. Both strains harbour point mutations in the erythroid transcription factor, Klf1. One (D11) generates a stop codon in the zinc finger domain and a homozygous null phenotype. The other (D45) generates an amino acid transversion (H350R) within a conserved linker between zinc fingers two and three. Homozygous MommeD45 mice have chronic microcytic anaemia which models the phenotype in a recently described family. This is the first genetic evidence that the linkers between the zinc fingers of transcription factors have a function beyond that of a simple spacer.
    Full-text · Article · Oct 2014 · Genomics
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    • "Previous studies have reported the incidence of accelerated apoptosis during the storage of platelet concentrates [45], [46], [47]. In this regard, a comprehensive knowledge of platelet apoptosis would be beneficial at several levels: first, apoptosis markers could be measured to predict the viability of the given platelet component; second, a means to rescue platelet apoptosis could be used to increase platelet lifespan and recirculation in the transfused patient, and to achieve primary hemostasis [48]. Indeed, the lifespan of platelets during circulation is 6-10 days [49]; thus, there is a significant decrease of platelet viability during 5 day storage [50], [51], [52]. "
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    ABSTRACT: Background Platelets participate in tissue repair and innate immune responses. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are well-characterized I-type lectins, which control apoptosis. Methodology/Principal Findings We characterized the expression of Siglec-7 in human platelets isolated from healthy volunteers using flow cytometry and confocal microscopy. Siglec-7 is primarily expressed on α granular membranes and colocalized with CD62P. Siglec-7 expression was increased upon platelet activation and correlated closely with CD62P expression. Cross-linking Siglec-7 with its ligand, ganglioside, resulted in platelet apoptosis without any significant effects on activation, aggregation, cell morphology by electron microscopy analysis or secretion. We show that ganglioside triggered four key pathways leading to apoptosis in human platelets: (i) mitochondrial inner transmembrane potential (ΔΨm) depolarization; (ii) elevated expression of pro-apoptotic Bax and Bak proteins with reduced expression of anti-apoptotic Bcl-2 protein; (iii) phosphatidylserine exposure and (iv), microparticle formation. Inhibition of NAPDH oxidase, PI3K, or PKC rescued platelets from apoptosis induced by Siglec-7 recruitment, suggesting that the platelet receptors P2Y1 and GPIIbIIIa are essential for ganglioside-induced platelet apoptosis. Conclusions/Significance The present work characterizes the role of Siglec-7 and platelet receptors in regulating apoptosis and death. Because some platelet pathology involves apoptosis (idiopathic thrombocytopenic purpura and possibly storage lesions), Siglec-7 might be a molecular target for therapeutic intervention/prevention.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Platelet life span is determined by opposing activities of anti- and pro-apoptotic Bcl-2 family proteins [46]. As proteasomal activity in tumor cells influences cellular level of these proteins and aspirin attenuated proteasome function in platelets (our earlier figure), we investigated if aspirin can regulate platelet lifespan in vivo in a rodent model. "
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    ABSTRACT: Aspirin is widely used in clinical settings as an anti-inflammatory and anti-platelet drug due its inhibitory effect on cyclooxygenase activity. Although the drug has long been considered to be an effective and safe therapeutic regime against inflammatory and cardiovascular disorders, consequences of its cyclooxygenase-independent attributes on platelets, the key players in thrombogenesis, beg serious investigation. In this report we explored the effect of aspirin on platelet lifespan in murine model and its possible cytotoxicity against human platelets in vitro. Aspirin administration in mice led to significant reduction in half-life of circulating platelets, indicative of enhanced rate of platelet clearance. Aspirin-treated human platelets were found to be phagocytosed more efficiently by macrophages, associated with attenuation in platelet proteasomal activity and upregulation of conformationally active Bax, which were consistent with enhanced platelet apoptosis. Although the dosage of aspirin administered in mice was higher than the therapeutic regimen against cardiovascular events, it is comparable with the recommended anti-inflammatory prescription. Thus, above observations provide cautionary framework to critically re-evaluate prophylactic and therapeutic dosage regime of aspirin in systemic inflammatory as well as cardiovascular ailments.
    Full-text · Article · Aug 2014 · PLoS ONE
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