M1 macrophage-derived exosomes alleviate leukemia by causing mitochondrial dysfunction

IF 3 3区 医学 Q2 HEMATOLOGY Annals of Hematology Pub Date : 2024-12-12 DOI:10.1007/s00277-024-06138-4
Wenjuan Li, Rufei Ma, Xiaozhen Fan, Zheng Xiao
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Abstract

Acute myeloid leukemia (AML) is one type of blood cancer that initially has a high cure rate but frequently relapses and leading to death. Therefore, there is an urgent need for innovative AML treatments. The leukemia C1498 cells were co-cultured with M1 macrophage-derived exosomes (M1-exo), and the proliferation and apoptosis of C1498 cells were investigated using CCK-8 and flow cytometry, respectively. qPCR and Western blot were applied to determine the PGAM5 expression in M1-exo treated C1498 cells. The role of M1-exo-derived PGAM5 in mitochondria was examined via fluorescence staining. The anti-inflammatory effects of M1-exo-derived PGAM5 and M1-exo were evaluated by flow cytometry, HE staining, and immunohistochemistry in xenograft and nude mouse tumorigenic models. M1-exo exhibited a potent capability to attenuate C1498 cell proliferation, and induce cell apoptosis. In vivo experimentation demonstrated that administration of M1-exo led to a reduction in leukocyte count, alleviated inflammatory infiltration, decreased liver and spleen weights, and significantly diminished tumor size. PGAM5 was elevated in M1-exo, and knockdown of PGAM5 in C1498 cells and M1-exo enhanced proliferation and reduced apoptosis in C1498 cells. Concurrently, M1-exo-derived PGAM5 decreased mitochondrial membrane potential and increased calcium influx in vitro. In vivo, studies showed that knockdown of PGAM5 in M1-exo elevated liver and spleen weights, augmented tumor size, and intensified hepatic inflammatory infiltration. Our study reveals that M1-exo induces mitochondrial dysfunction against leukemia through PGAM5.

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M1巨噬细胞来源的外泌体通过引起线粒体功能障碍减轻白血病。
急性髓性白血病(AML)是一种最初治愈率高但经常复发并导致死亡的血癌。因此,迫切需要创新AML治疗方法。将白血病C1498细胞与M1巨噬细胞来源的外泌体(M1-exo)共培养,采用CCK-8和流式细胞术分别观察C1498细胞的增殖和凋亡情况。采用qPCR和Western blot检测M1-exo处理的C1498细胞中PGAM5的表达。荧光染色检测m1 -外显子来源的PGAM5在线粒体中的作用。采用流式细胞术、HE染色、免疫组化等方法对移植瘤和裸鼠致瘤模型中M1-exo源性PGAM5和M1-exo的抗炎作用进行了评价。M1-exo表现出抑制C1498细胞增殖和诱导细胞凋亡的能力。体内实验表明,给药M1-exo导致白细胞计数减少,炎症浸润减轻,肝脏和脾脏重量减轻,肿瘤大小明显缩小。PGAM5在M1-exo中表达升高,PGAM5在C1498细胞和M1-exo中的表达下调可增强C1498细胞的增殖,减少细胞凋亡。同时,m1 -外源性PGAM5降低了线粒体膜电位,增加了体外钙内流。在体内,研究表明,m1 - ex1中PGAM5的敲低会增加肝脏和脾脏的重量,增大肿瘤大小,并加剧肝脏炎症浸润。我们的研究表明M1-exo通过PGAM5诱导线粒体功能障碍对抗白血病。
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来源期刊
Annals of Hematology
Annals of Hematology 医学-血液学
CiteScore
5.60
自引率
2.90%
发文量
304
审稿时长
2 months
期刊介绍: Annals of Hematology covers the whole spectrum of clinical and experimental hematology, hemostaseology, blood transfusion, and related aspects of medical oncology, including diagnosis and treatment of leukemias, lymphatic neoplasias and solid tumors, and transplantation of hematopoietic stem cells. Coverage includes general aspects of oncology, molecular biology and immunology as pertinent to problems of human blood disease. The journal is associated with the German Society for Hematology and Medical Oncology, and the Austrian Society for Hematology and Oncology.
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