PI3K alpha and delta promote hematopoietic stem cell activation
PI3K alpha and delta promote hematopoietic stem cell activation
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DOI：
10.1172/jci.insight.125832
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发表时间：
2019-07-11
期刊：
影响因子：
8
通讯作者：
Gritsman, Kira
中科院分区：
文献类型：
--
作者：
Hemmati, Shayda;Sinclair, Taneisha;Gritsman, Kira
许多对造血重要的细胞因子和趋化因子都会激活 PI3K 信号通路。由于该通路在癌症中经常发生突变和激活，因此 PI3K 抑制剂已被开发用于治疗多种恶性肿瘤，并且目前正在临床上与化疗相结合进行测试。然而，PI3K 在成体造血干细胞 (HSC) 中的作用，特别是在造血应激期间的作用仍不清楚。我们之前表明，单个 PI3K 催化亚型 p110 α 和 p110 beta 在 HSC 功能中具有可有可无的作用，这表明 HSC 中 PI3K 亚型之间存在冗余。我们现在证明，双敲除 (DKO) HSC 中 p110 α 和 p110 δ 的同时删除揭示了 5-氟尿嘧啶 (5-FU) 化疗后 HSC 循环中它们的冗余需求。相比之下，DKO HSC 仍然能够响应其他应激刺激（例如 LPS）而退出静止状态。我们发现 DKO HSC 和祖细胞对离体炎症信号的感知受损，并且 LPS 后骨髓 (BM) 中 IL-1 β 和 MIG 的水平高于 5-FU 给药后。此外，体内外源性IL-1β可以诱导DKO HSC进入细胞周期。我们的研究结果对于 PI3K 抑制剂与化疗联合使用具有临床意义。
Many cytokines and chemokines that are important for hematopoiesis activate the PI3K signaling pathway. Because this pathway is frequently mutated and activated in cancer, PI3K inhibitors have been developed for the treatment of several malignancies and are now being tested in the clinic in combination with chemotherapy. However, the role of PI3K in adult hematopoietic stem cells (HSCs), particularly during hematopoietic stress, is still unclear. We previously showed that the individual PI3K catalytic isoforms p110 alpha and p110 beta have dispensable roles in HSC function, suggesting redundancy between PI3K isoforms in HSCs. We now demonstrate that simultaneous deletion of p110 alpha and p110 delta in double-knockout (DKO) HSCs uncovers their redundant requirement in HSC cycling after 5-fluorouracil (5-FU) chemotherapy administration. In contrast, DKO HSCs were still able to exit quiescence in response to other stress stimuli, such as LPS. We found that DKO HSCs and progenitors had impaired sensing of inflammatory signals ex vivo, and that levels of IL-1 beta and MIG were higher in the bone marrow (BM) after LPS than after 5-FU administration. Furthermore, exogenous in vivo administration of IL-1 beta could induce cell cycle entry of DKO HSCs. Our findings have clinical implications for the use of PI3K inhibitors in combination with chemotherapy.