Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, State Key Laboratory of Experimental Hematology, Shanghai, China.
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China.
J Clin Invest. 2021 Jan 4;131(1). doi: 10.1172/JCI138986.
Small extracellular vesicles (SEVs) are functional messengers of certain cellular niches that permit noncontact cell communications. Whether niche-specific SEVs fulfill this role in cancer is unclear. Here, we used 7 cell type-specific mouse Cre lines to conditionally knock out Vps33b in Cdh5+ or Tie2+ endothelial cells (ECs), Lepr+ BM perivascular cells, Osx+ osteoprogenitor cells, Pf4+ megakaryocytes, and Tcf21+ spleen stromal cells. We then examined the effects of reduced SEV secretion on progression of MLL-AF9-induced acute myeloid leukemia (AML), as well as normal hematopoiesis. Blocking SEV secretion from ECs, but not perivascular cells, megakaryocytes, or spleen stromal cells, markedly delayed the leukemia progression. Notably, reducing SEV production from ECs had no effect on normal hematopoiesis. Protein analysis showed that EC-derived SEVs contained a high level of ANGPTL2, which accelerated leukemia progression via binding to the LILRB2 receptor. Moreover, ANGPTL2-SEVs released from ECs were governed by VPS33B. Importantly, ANGPTL2-SEVs were also required for primary human AML cell maintenance. These findings demonstrate a role of niche-specific SEVs in cancer development and suggest targeting of ANGPTL2-SEVs from ECs as a potential strategy to interfere with certain types of AML.
小细胞外囊泡 (SEV) 是某些细胞龛的功能信使，允许非接触式细胞通讯。在癌症中，特定龛位的 SEV 是否发挥了这种作用尚不清楚。在这里，我们使用 7 种细胞类型特异性的小鼠 Cre 线，在 Cdh5+或 Tie2+内皮细胞（EC）、Lepr+BM 血管周细胞、Osx+成骨前体细胞、Pf4+巨核细胞和 Tcf21+脾基质细胞中条件性敲除 Vps33b。然后，我们研究了减少 SEV 分泌对 MLL-AF9 诱导的急性髓系白血病（AML）进展以及正常造血的影响。阻断 EC 而不是血管周细胞、巨核细胞或脾基质细胞的 SEV 分泌，显著延缓了白血病的进展。值得注意的是，减少 EC 产生的 SEV 对正常造血没有影响。蛋白分析表明，EC 来源的 SEVs 含有高水平的 ANGPTL2，通过与 LILRB2 受体结合加速白血病进展。此外，EC 释放的 ANGPTL2-SEVs 受 VPS33B 控制。重要的是，ANGPTL2-SEVs 对于维持原发性人 AML 细胞也是必需的。这些发现表明特定龛位的 SEV 在癌症发展中的作用，并表明靶向 EC 中的 ANGPTL2-SEVs 作为干扰某些类型 AML 的潜在策略。
