Ptpn11激活突变骨髓细胞来源的外泌体在骨髓增殖性肿瘤中的作用

The role of exosomes derived from Ptpn11 activating mutant bone marrow cells in myeloproliferative neoplasma

目的研究Ptpn11^(E76K/+);Mx1-Cre^(+)激活突变骨髓细胞来源的外泌体在骨髓增殖性肿瘤(MPN)进程中发挥的作用。方法分离Ptpn11^(E76K/+);Mx1-Cre^(+)激活突变骨髓细胞来源的外泌体,与含有正常造血干细胞(HSCs)的LSK细胞进行体外培养,通过尾静脉将突变骨髓细胞来源的外泌体注射到野生C57BL小鼠体内,观察外泌体在体内外发挥的作用,最后通过细胞因子试剂盒检测突变骨髓细胞来源的外泌体发生的改变。结果突变骨髓细胞来源的外泌体会携带相关炎性因子,加速正常HSCs的髓系分化能力,导致正常小鼠发生MPN样的表型。使用炎性因子拮抗剂之后小鼠的MPN症状有所缓解,外泌体中相关炎性因子的表达也降低。结论Ptpn11^(E76K/+);Mx1-Cre^(+)激活突变骨髓细胞来源的外泌体携带炎性因子导致小鼠发生MPN样表型,外泌体及其携带的炎性因子都可以作为MPN治疗的潜在靶点。

Objective To explore the role of Ptpn11^(E76K/+);Mx1-Cre^(+)activating mutant bone marrow-derived exosomes in the occurrence of myeloproliferative neoplasma(MPN).Methods Ptpn11^(E76K/+);Mx1-Cre^(+)activating mutant bone marrow-derived exosomes were co-cultured with normal hematopoietic stem cells in vitro,and at the same time,mutant exosomes were injected into normal mice through the tail vein to observe the effects of exosomes in vivo.The mouse cytokine array panel was used to detect the specific changes in the exosomes derived from the mutant bone marrow.Results Exosomes derived from mutant bone marrow could carry series of inflammatory factors,which accelerated the myeloid differentiation of normal hematopoietic stem cells,leading to the occurrence of MPN in normal mice.After inhibiting inflammatory factors,the symptoms of MPN in mice were relieved,and the expression of inflammatory factors in exosomes also decreased.Conclusion Ptpn11^(E76K/+);Mx1-Cre^(+)activating mutant bone marrow-derived exosomes can trigger MPN in mice via inflammatory factors.Both exosomes and the inflammatory factors they carry can be potential targets for MPN therapy.