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J. Cell Biol. 160 (4): 577-587

Copyright © 2003 by the Rockefeller University Press.

Article

Compartmentalized megakaryocyte death generates functional platelets committed to caspase-independent death

Murray C.H. Clarke1, John Savill1, David B. Jones3, Brendon S. Noble2, and Simon B. Brown1

1 Centre for Inflammation Research, Department of Clinical and Surgical Sciences (Internal Medicine), Royal Infirmary Edinburgh, Edinburgh EH3 9YW, UK
2 Musculoskeletal Research Unit, Department of Clinical and Surgical Sciences (Internal Medicine), Royal Infirmary Edinburgh, Edinburgh EH3 9YW, UK
3 Philipps-University Marburg, Department of Experimental Orthopaedics and Biomechanics, 35033 Marburg, Germany

Address correspondence to S.B. Brown, Centre for Inflammation Research, Medical School, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK. Tel.: 44-131-6511606. Fax: 44-131-6511607. E-mail: simon.brown{at}ed.ac.uk

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.

Key Words: mitochondria; Fas; apoptosis; caspases; thrombopoiesis

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