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Prepublished online as a Blood First Edition Paper on June 7, 2002; DOI 10.1182/blood-2002-03-0686. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-03-0686v1 100/4/1310    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by de Botton, S. Articles by Debili, N. Search for Related Content PubMed PubMed Citation Articles by de Botton, S. Articles by Debili, N. Related Collections Hematopoiesis and Stem Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 August 2002, Vol. 100, No. 4, pp. 1310-1317 HEMATOPOIESIS Platelet formation is the consequence of caspase activation within megakaryocytes Stephane de Botton, Siham Sabri, Eric Daugas, Yael Zermati, Jacques Emmanuel Guidotti, Olivier Hermine, Guido Kroemer, William Vainchenker, and Najet Debili From the Institut National de la Santé et de la Recherche Médicale (INSERM) U362 and the Centre National de la Recherche Scientifique (CNRS, Unité Mixte de Recherche 1599), Institut Gustave Roussy, Institut Fédératif de Recherche 54, Villejuif, France; CNRS, Unité Mixte de Recherche 8603, Université René Descartes (Paris V), Institut Fédératif de Recherche Necker, and INSERM U129, Institut Cochin de Génétique Moléculaire, Paris, France; and Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France. Platelets are formed from mature megakaryocytes (MKs) and arise from the development of long and thin cytoplasmic extensions called proplatelets. After platelet release, the senescent MKs (nucleus surrounded by some cytoplasm) undergo cell death by apoptosis. To explore the precise role of apoptosis in proplatelet formation, we grew human MKs from CD34+ cells and assessed the possible role of caspases. Proteolytic maturation of procaspase-3 and procaspase-9 was detected by immunoblots in maturing MKs as well as in proplatelet-bearing MKs and senescent MKs. Cleavage of caspase substrates such as gelsolin or poly adenosine diphosphate (ADP)-ribose polymerase (PARP) was also detected. Interestingly, activated forms of caspase-3 were detected in maturing MKs, before proplatelet formation, with a punctuate cytoplasmic distribution, whereas a diffuse staining pattern was seen in senescent and apoptotic MKs. This localized activation of caspase-3 was associated with a mitochondrial membrane permeabilization as assessed by the release of cytochrome c, suggesting an activation of the intrinsic pathway. Moreover, these MKs with localized activated caspase-3 had no detectable DNA fragmentation. In contrast, when apoptosis was induced by staurosporine, diffuse caspase activation was seen; these MKs had signs of DNA fragmentation, and no proplatelet formation occurred. The pan-caspase inhibitor z-VAD.fmk as well as more specific inhibitors of caspase-3 and caspase-9 blocked proplatelet formation, whereas an inhibitor of calpeptin had no effect. Overexpression of Bcl-2 also inhibited proplatelet formation in maturing MKs. Thus, localized caspase activation is causal to proplatelet formation. 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