IFN-γ-induced apoptosis of human embryonic stem cell derived oligodendrocyte progenitor cells is restricted by CXCR2 signaling.
IFN-γ-induced apoptosis of human embryonic stem cell derived oligodendrocyte progenitor cells is restricted by CXCR2 signaling.
复制标题
IFN-γ 诱导的人胚胎干细胞衍生的少突胶质细胞祖细胞的凋亡受到 CXCR2 信号传导的限制。
DOI：
10.1016/j.scr.2012.06.005
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发表时间：
2012
影响因子：
1.2
通讯作者：
Lane,ThomasE
中科院分区：
文献类型：
--
作者：
Tirotta,Emanuele;Kirby,LeslieA;Hatch,MayaN;Lane,ThomasE
将人胚胎干细胞 (hESC) 衍生的 OPC 移植到脱髓鞘动物模型中可实现髓鞘再生和临床恢复，支持细胞替代疗法促进受损神经组织修复的可行性。我们对修复相关机制的理解存在一个关键差距，即局部微环境对移植细胞存活的影响。我们已经确定，用多效细胞因子 IFN-γ 处理人 ESC 衍生的 OPC 会促进细胞凋亡，这与释放到细胞质中的线粒体细胞色素 c 以及随后的 caspase 3 激活相关。 IFN-γ 诱导的细胞凋亡部分是由 IFN-γ 处理的细胞分泌 CXC 趋化因子配体 10 (CXCL10) 介导的。配体 CXCL1 通过趋化因子受体 CXCR2 发出信号，通过抑制细胞凋亡以强直方式发挥作用，这与胞质细胞色素 c 水平降低和 caspase 3 裂解受损有关。这些发现支持 IFN-γ 和 CXCL10 通过促进 OPC 细胞凋亡而在神经病理学中发挥作用。此外，这些数据表明，用于治疗人类神经系统疾病/损伤的 hOPC 很容易因暴露于炎症环境中存在的局部炎症细胞因子而死亡。
Engraftment of human embryonic stem cell (hESC)-derived OPCs in animal models of demyelination results in remyelination and clinical recovery, supporting the feasibility of cell replacement therapies in promoting repair of damaged neural tissue. A critical gap in our understanding of the mechanisms associated with repair revolves around the effects of the local microenvironment on transplanted cell survival. We have determined that treatment of human ESC-derived OPCs with the pleiotropic cytokine IFN-γ promotes apoptosis that is associated with mitochondrial cytochrome c released into the cytosol with subsequent caspase 3 activation. IFN-γ-induced apoptosis is mediated, in part, by secretion of the CXC chemokine ligand 10 (CXCL10) from IFN-γ-treated cells. Signaling through the chemokine receptor CXCR2 by the ligand CXCL1 functions in a tonic manner by muting apoptosis and this is associated with reduced levels of cytosolic cytochrome c and impaired cleavage of caspase 3. These findings support a role for both IFN-γ and CXCL10 in contributing to neuropathology by promoting OPC apoptosis. In addition, these data suggest that hOPCs used for therapeutic treatment for human neurologic disease/damage are susceptible to death through exposure to local inflammatory cytokines present within the inflammatory milieu.