Alternative cell death of Apaf1-deficient neural progenitor cells induced by withdrawal of EGF or insulin
Alternative cell death of Apaf1-deficient neural progenitor cells induced by withdrawal of EGF or insulin
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DOI：
10.1016/j.bbagen.2009.11.008
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发表时间：
2010-03-01
影响因子：
3
通讯作者：
Yoshida, Hiroki
中科院分区：
文献类型：
--
作者：
Shiraishi, Hiroshi;Okamoto, Hideaki;Yoshida, Hiroki
背景：各种形式的细胞死亡，如凋亡、自噬和非溶酶体类型，都涉及正常的生理过程。凋亡蛋白酶激活因子1 （Apaf1）是细胞内在凋亡通路的重要组成部分。Apaf1的缺乏导致发育中的中枢神经系统中神经祖细胞（npc）的积累，从而导致围产期死亡。然而，一小部分突变小鼠能够存活并发育成熟。这种正常突变体的发生暗示了神经发生过程中细胞死亡的替代途径。方法：在无生长因子的培养基中培养野生型或apaf1缺失胚制备的npc，观察细胞死亡、caspase激活和形态变化。研究了活性氧（ROS）的生成和抗氧化剂的作用。结果：野生型NPCs在停用表皮生长因子（EGF）或胰岛素24小时内发生细胞凋亡，而分离缺失型NPCs发生细胞死亡，但无凋亡迹象。自噬并不一定伴随着细胞死亡。细胞死亡类似于坏死坏死样的程序性细胞死亡。坏死下垂抑制剂坏死他汀-1不能抑制细胞死亡。在缺乏生长因子的NPCs中检测到ROS积累，抗氧化剂部分抑制apaf1缺失的NPCs的非凋亡细胞死亡。结论：这些数据表明，停用EGF或胰岛素后，apaf1缺陷细胞发生非凋亡性细胞死亡。ROS的产生可能部分参与了细胞死亡。一般意义：NPCs的非凋亡性细胞死亡可能是分离缺失胚胎发育中的一种代偿机制。(C) 2009 Elsevier By。版权所有。
Background: Various forms of cell death, such as apoptotic, autophagic and non-lysosomal types, are implicated in normal physiological processes. Apoptotic protease activating factor 1 (Apaf1) is an important component of the intrinsic apoptotic pathway. Deficiency of Apaf1 results in an accumulation of neural progenitor cells (NPCs) in the developing central nervous system and thus, in perinatal lethality. A small percentage of the mutant mice, however, are viable and grow to maturity. The occurrence of such normal mutants implicates alternative cell death pathways during neurogenesis.Methods: NPCs prepared from wild-type or Apaf1-deficient embryos were cultured in growth factor-deprived medium and examined for cell death, caspase activation and morphological alterations. Generation of reactive oxygen species (ROS) and the effects of antioxidants were examined.Results: Wild-type NPCs underwent apoptosis within 24 hours of withdrawal of epidermal growth factor (EGF) or insulin, whereas Apart-deficient NPCs underwent cell death but showed no signs of apoptosis. Autophagy was not necessarily accompanied by cell death. Cell death of the Apart-deficient NPCs resembled necroptosis necrosis-like programmed cell death. The necroptosis inhibitor necrostatin-1, however, failed to inhibit the cell death. ROS accumulation was detected in NPCs deprived of growth factors, and an antioxidant partially suppressed the non-apoptotic cell death of Apaf1-deficient NPCs.Conclusions: These data indicate that after withdrawal EGF or insulin withdrawal, the Apaf1-deficient cells underwent non-apoptotic cell death. ROS generation may partially participate in the cell death. General Significance: Non-apoptotic cell death in NPCs may be a compensatory mechanism in the developing CNS of Apart-deficient embryos. (C) 2009 Elsevier By. All rights reserved.