title: Compartmentalized megakaryocyte death generates functional platelets committed to caspase-independent death.
abstract: Caspase-directed apoptosis usually fragments cells, releasing nonfunctional, prothrombogenic, membrane-bound apoptotic bodies marked for rapid engulfment by macrophages. Blood platelets are functional anucleate cells generated by specialized fragmentation of their progenitors, megakaryocytes (MKs), but committed to a constitutive caspase-independent death. Constitutive formation of the proplatelet-bearing MK was recently reported to be caspase-dependent, apparently involving mitochondrial release of cytochrome c, a known pro-apoptogenic factor. We extend those studies and report that activation of caspases in MKs, either constitutively or after Fas ligation, yields platelets that are functionally responsive and evade immediate phagocytic clearance, and retain mitochondrial transmembrane potential until constitutive platelet death ensues. Furthermore, the exclusion from the platelet progeny of caspase-9 present in the progenitor accounts for failure of mitochondrial release of cytochrome c to activate caspase-3 during platelet death. Thus, progenitor cell death by apoptosis can result in birth of multiple functional anucleate daughter cells.
authors.affiliation: Centre for Inflammation Research, Department of Clinical and Surgical Sciences (Internal Medicine), Royal Infirmary Edinburgh, Edinburgh EH3 9YW, UK.
authors.forename: Murray C H
authors.initials: MC
authors.lastname: Clarke
authors.forename: John
authors.initials: J
authors.lastname: Savill
authors.forename: David B
authors.initials: DB
authors.lastname: Jones
authors.forename: Brendon S
authors.initials: BS
authors.lastname: Noble
authors.forename: Simon B
authors.initials: SB
authors.lastname: Brown
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D001792:Blood Platelets / Q000502:physiology*; D001842:Bone and Bones / Q000166:cytology; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008533:Megakaryocytes / Q000502:physiology* / Q000648:ultrastructure; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: C506592:APAF1 protein, human; D000590:Amino Acid Chloromethyl Ketones; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D008024:Ligands; D011506:Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D020169:Caspases