Purinergic P2Y14 receptor modulates stress-induced hematopoietic stem/progenitor cell senescence
Purinergic P2Y14 receptor modulates stress-induced hematopoietic stem/progenitor cell senescence
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DOI：
10.1172/jci61636
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发表时间：
2014-07-01
影响因子：
15.9
通讯作者：
Lee, Byeong Chel
中科院分区：
文献类型：
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作者：
Cho, Joonseok;Yusuf, Rushdia;Lee, Byeong Chel
P2 Y家族的嘌呤能受体是G蛋白偶联的表面受体，其响应于细胞外核苷酸并且可以介导对局部细胞损伤的响应。P2 Y依赖性信号传导通过改变血小板和内皮活化以及免疫细胞吞噬作用而促成组织损伤的血栓形成和/或炎性后果。在这里，我们已经证明，P2 Y（14）改变细胞衰老和细胞死亡，以响应组织应力，从而使造血干/祖细胞功能的保护。在小鼠中，P2 Y（14）缺乏在稳态条件下没有明显的影响;然而，辐射应激、衰老、连续暴露于化疗和连续骨髓移植会增加缺乏P2 Y的动物的衰老（14）。增强衰老与ROS增加、p16（INK 4a）表达升高和Rb低磷酸化一致，并且通过用ROS清除剂处理或抑制p38/MAPK和JNK来抑制。用百日咳毒素处理WT细胞重现了P2 Y（14）表型，表明P2 Y（14）通过Gi/o蛋白依赖性途径介导抗衰老作用。缺乏P2 Y的原始造血细胞（14）在受辐射小鼠中恢复造血的能力受到损害。总之，这些数据表明，造血系统干/祖细胞上的P2 Y（14）通过监测和响应组织应激的细胞外表现来抑制细胞衰老，并表明P2 Y（14）介导的反应防止损伤后再生能力的过早下降。
Purinergic receptors of the P2Y family are G protein-coupled surface receptors that respond to extracellular nucleotides and can mediate responses to local cell damage. P2Y-dependent signaling contributes to thrombotic and/or inflammatory consequences of tissue injury by altering platelet and endothelial activation and immune cell phagocytosis. Here, we have demonstrated that P2Y(14) modifies cell senescence and cell death in response to tissue stress, thereby enabling preservation of hematopoietic stem/progenitor cell function. In mice, P2Y(14) deficiency had no demonstrable effect under homeostatic conditions; however, radiation stress, aging, sequential exposure to chemotherapy, and serial bone marrow transplantation increased senescence in animals lacking P2Y(14). Enhanced senescence coincided with increased ROS, elevated pl6(INK4a) expression, and hypophosphorylated Rb and was inhibited by treatment with a ROS scavenger or inhibition of p38/MAPK and JNK. Treatment of WT cells with pertussis toxin recapitulated the P2Y(14) phenotype, suggesting that P2Y(14) mediates antisenescence effects through Gi/o protein-dependent pathways. Primitive hematopoietic cells lacking P2Y(14) were compromised in their ability to restore hematopoiesis in irradiated mice. Together, these data indicate that P2Y(14) on stem/progenitor cells of the hematopoietic system inhibits cell senescence by monitoring and responding to the extracellular manifestations of tissue stress and suggest that P2Y(14)-mediated responses prevent the premature decline of regenerative capacity after injury.