Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets
Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets
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DOI：
10.1084/jem.20110750
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发表时间：
2011-09-26
影响因子：
15.3
通讯作者：
Kile, Benjamin T.
中科院分区：
文献类型：
--
作者：
Josefsson, Emma C.;James, Chloe;Kile, Benjamin T.
据信巨核细胞经历专门形式的凋亡以脱落血小板。相反，一系列病理生理损伤，包括化疗，被认为是通过诱导巨核细胞及其祖细胞的凋亡性死亡而引起血小板减少症。为了解决这一矛盾，我们产生了造血或巨核细胞特异性缺失凋亡的基本介质，巴克和Bax的小鼠。我们发现血小板的产生是不受干扰的。与此形成鲜明对比的是，促生存蛋白Bcl-x（L）的缺失导致巨核细胞凋亡和血小板脱落失败。这可以通过删除巴克和Bax来挽救。我们研究了在其他细胞类型中激活内在凋亡途径的三种药物对巨核细胞的影响：依托泊苷，星形孢菌素和BH 3模拟物ABT-737。所有这三个触发线粒体损伤，半胱天冬酶激活和细胞死亡。缺失巴克和Bax使巨核细胞对依托泊苷和ABT-737耐药。在体内，具有巴克（-/-）Bax（-/-）造血系统的小鼠被保护免于由化疗剂卡铂诱导的血小板减少症。因此，巨核细胞不会激活生成血小板的内在途径;相反，它们必须通过前血小板形成和血小板脱落来抑制它的生存和安全进展。
It is believed that megakaryocytes undergo a specialized form of apoptosis to shed platelets. Conversely, a range of pathophysiological insults, including chemotherapy, are thought to cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. To resolve this paradox, we generated mice with hematopoietic-or megakaryocyte-specific deletions of the essential mediators of apoptosis, Bak and Bax. We found that platelet production was unperturbed. In stark contrast, deletion of the prosurvival protein Bcl-x(L) resulted in megakaryocyte apoptosis and a failure of platelet shedding. This could be rescued by deletion of Bak and Bax. We examined the effect on megakaryocytes of three agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and the BH3 mimetic ABT-737. All three triggered mitochondrial damage, caspase activation, and cell death. Deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and ABT-737. In vivo, mice with a Bak(-/-) Bax(-/-) hematopoietic system were protected against thrombocytopenia induced by the chemotherapeutic agent carboplatin. Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets; rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding.