Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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

Copyright © 2003 by the Rockefeller University Press.


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}

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

Proposed megakaryocytic regulon of p53: the genes engaged to control cell cycle and apoptosis during megakaryocytic differentiation.
P. A. Apostolidis, S. Lindsey, W. M. Miller, and E. T. Papoutsakis (2012)
Physiol Genomics 44, 638-650
   Abstract »    Full Text »    PDF »
Death-defying apoptotic caspases in thrombopoiesis.
A. B. Cantor (2012)
Blood 119, 4098-4099
   Full Text »    PDF »
A functional variant in the core promoter of the CD95 cell death receptor gene predicts prognosis in acute promyelocytic leukemia.
N. J. Sunter, K. Scott, R. Hills, D. Grimwade, S. Taylor, L. J. Worrillow, S. E. Fordham, V. J. Forster, G. Jackson, S. Bomken, et al. (2012)
Blood 119, 196-205
   Abstract »    Full Text »    PDF »
Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets.
E. C. Josefsson, C. James, K. J. Henley, M. A. Debrincat, K. L. Rogers, M. R. Dowling, M. J. White, E. A. Kruse, R. M. Lane, S. Ellis, et al. (2011)
J. Exp. Med. 208, 2017-2031
   Abstract »    Full Text »    PDF »
Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia.
L. Yang, L. Wang, C.-h. Zhao, X.-j. Zhu, Y. Hou, P. Jun, and M. Hou (2010)
Blood 116, 4307-4316
   Abstract »    Full Text »    PDF »
The regulation of proplatelet production.
A. E. Geddis (2009)
Haematologica 94, 756-759
   Full Text »    PDF »
15-deoxy-{Delta}12,14-PGJ2 enhances platelet production from megakaryocytes.
J. J. O'Brien, S. L. Spinelli, J. Tober, N. Blumberg, C. W. Francis, M. B. Taubman, J. Palis, K. E. Seweryniak, J. M. Gertz, and R. P. Phipps (2008)
Blood 112, 4051-4060
   Abstract »    Full Text »    PDF »
Metalloproteinase regulation improves in vitro generation of efficacious platelets from mouse embryonic stem cells.
H. Nishikii, K. Eto, N. Tamura, K. Hattori, B. Heissig, T. Kanaji, A. Sawaguchi, S. Goto, J. Ware, and H. Nakauchi (2008)
J. Exp. Med. 205, 1917-1927
   Abstract »    Full Text »    PDF »
Anaplasma phagocytophilum infects cells of the megakaryocytic lineage through sialylated ligands but fails to alter platelet production.
J. L. Granick, D. V. Reneer, J. A. Carlyon, and D. L. Borjesson (2008)
J. Med. Microbiol. 57, 416-423
   Abstract »    Full Text »    PDF »
Systems analysis of effector caspase activation and its control by X-linked inhibitor of apoptosis protein.
M. Rehm, H. J. Huber, H. Dussmann, and J. H. Prehn (2006)
EMBO J. 25, 4338-4349
   Abstract »    Full Text »    PDF »
A novel role for microtubules in apoptotic chromatin dynamics and cellular fragmentation.
D. K. Moss, V. M. Betin, S. D. Malesinski, and J. D. Lane (2006)
J. Cell Sci. 119, 2362-2374
   Abstract »    Full Text »    PDF »
Mechanisms of organelle transport and capture along proplatelets during platelet production.
J. L. Richardson, R. A. Shivdasani, C. Boers, J. H. Hartwig, and J. E. Italiano Jr (2005)
Blood 106, 4066-4075
   Abstract »    Full Text »    PDF »
CD46 Plays a Key Role in Tailoring Innate Immune Recognition of Apoptotic and Necrotic Cells.
K. Elward, M. Griffiths, M. Mizuno, C. L. Harris, J. W. Neal, B. P. Morgan, and P. Gasque (2005)
J. Biol. Chem. 280, 36342-36354
   Abstract »    Full Text »    PDF »
The Bone Marrow Vascular Niche: Home of HSC Differentiation and Mobilization.
H.-G. Kopp, S. T. Avecilla, A. T. Hooper, and S. Rafii (2005)
Physiology 20, 349-356
   Abstract »    Full Text »    PDF »
Role of Mitochondrial Permeability Transition Pore in Coated-Platelet Formation.
G. Remenyi, R. Szasz, P. Friese, and G. L. Dale (2005)
Arterioscler Thromb Vasc Biol 25, 467-471
   Abstract »    Full Text »    PDF »
Caspase-12: a developmental link between G-protein-coupled receptors and integrin {alpha}IIb{beta}3 activation.
S. W. Kerrigan, M. Gaur, R. P. Murphy, S. J. Shattil, and A. D. Leavitt (2004)
Blood 104, 1327-1334
   Abstract »    Full Text »    PDF »
Proplatelet formation of megakaryocytes is triggered by autocrine-synthesized estradiol.
Y. Nagata, J. Yoshikawa, A. Hashimoto, M. Yamamoto, A. H. Payne, and K. Todokoro (2003)
Genes & Dev. 17, 2864-2869
   Abstract »    Full Text »    PDF »
Metalloproteinase inhibitors improve the recovery and hemostatic function of in vitro-aged or -injured mouse platelets.
W. Bergmeier, P. C. Burger, C. L. Piffath, K. M. Hoffmeister, J. H. Hartwig, B. Nieswandt, and D. D. Wagner (2003)
Blood 102, 4229-4235
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882