Exosomes from Bone Marrow Microenvironment-Derived Mesenchymal Stem Cells Affect CML Cells Growth and Promote Drug Resistance to Tyrosine Kinase Inhibitors.
Exosomes from Bone Marrow Microenvironment-Derived Mesenchymal Stem Cells Affect CML Cells Growth and Promote Drug Resistance to Tyrosine Kinase Inhibitors.
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来自骨髓微环境的间充质干细胞的外泌体影响 CML 细胞生长并促进对酪氨酸激酶抑制剂的耐药性
DOI：
10.1155/2020/8890201
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发表时间：
2020
影响因子：
4.3
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Zhang X;Yang Y;Yang Y;Chen H;Tu H;Li J
尽管使用酪氨酸激酶抑制剂治疗慢性粒细胞白血病(CML)取得了重大进展，但患者在停药后复发，需要长期药物治疗。这反映出CML克隆尚未完全消除。CML细胞维持的确切机制尚不完全清楚。骨髓微环境构成了白血病细胞的庇护所。间充质干细胞(MSC)是骨髓微环境的重要组成部分。它在慢性粒细胞白血病的发生发展和耐药中起着重要作用。越来越多的证据表明，外切体在细胞间的通讯中起着至关重要的作用。我们通过连续离心法成功地从人骨髓微环境来源的间充质干细胞(hBMMSC-Exo)中分离纯化了外体。在本研究中，我们研究了hBMMSC-Exo对慢性粒细胞白血病细胞增殖、凋亡和耐药性的影响。结果表明，hBMMSC-Exo可通过miR-15a抑制CML细胞体外增殖，并使细胞周期停滞于G0/G1期。然而，从BALB/c nu/nu小鼠的研究中获得的结果显然与体外结果相矛盾。事实上，hBMMSC-Exo在体内增加了肿瘤的发生率并促进了肿瘤的生长。进一步研究表明，抗凋亡蛋白Bcl2的表达增加，而Caspase3的表达减少。体内移植瘤模型研究表明，hBMMSC-Exo可促进CML细胞的增殖，降低其对酪氨酸激酶抑制剂的敏感性，导致耐药。这些结果表明，hBMMSC-Exo通过细胞-外源性保护机制支持CML细胞的维持和对BM的耐药性。他们还提示hBMMSC-Exo可能是克服微环境介导的耐药的潜在靶点。
Although major advances have been achieved in the treatment of chronic myeloid leukemia (CML) by using tyrosine kinase inhibitors, patients relapse after withdrawal and need long-term medication. This reflects the CML clones have not been eliminated completely. The precise mechanisms for the maintenance of CML cells are not yet fully understood. The bone marrow microenvironment constitutes the sanctuary for leukemic cells. Mesenchymal stem cells (MSC) are an important component of the bone marrow microenvironment (BM). It plays an important role in the development and drug resistance of CML. Accumulating evidence indicates that exosomes play a vital role in cell-to-cell communication. We successfully isolated and purified exosomes from human bone marrow microenvironment-derived mesenchymal stem cells (hBMMSC-Exo) by serial centrifugation. In the present study, we investigated the effect of hBMMSC-Exo on the proliferation, apoptosis, and drug resistance of CML cells. The results demonstrated that hBMMSC-Exo had the ability to inhibit the proliferation of CML cells in vitro via miR-15a and arrest cell cycle in the G0/G1 phase. However, the results obtained from BALB/c nu/nu mice studies apparently contradicted the in vitro results. In fact, hBMMSC-Exo increased tumor incidence and promoted tumor growth in vivo. Further study showed the antiapoptotic protein Bcl-2 expression increased, whereas the Caspase3 expression decreased. Moreover, the in vivo study in the xenograft tumor model showed that hBMMSC-Exo promoted the proliferation and decreased the sensitivity of CML cells to tyrosine kinase inhibitors, resulting in drug resistance. These results demonstrated that hBMMSC-Exo supported the maintenance of CML cells and drug resistance in BM by cell-extrinsic protective mechanisms. They also suggested that hBMMSC-Exo might be a potential target to overcome the microenvironment-mediated drug resistance.
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影响因子：
15.9
作者：
Roccaro, Aldo M.;Sacco, Antonio;Ghobrial, Irene M.
通讯作者：
Ghobrial, Irene M.
MiR-15a/16通过抑制多发性骨髓瘤中Bcl-2、VEGF-A和IL-17的表达来调节骨髓瘤细胞的生长、血管生成和抗肿瘤免疫
影响因子：
2.7
作者：
Li, Yanjie;Zhang, Bingyun;Li, Zhenyu
通讯作者：
Li, Zhenyu
影响因子：
2.7
作者：
Quintarelli, Concetta;De Angelis, Biagio;Pane, Fabrizio
通讯作者：
Pane, Fabrizio
影响因子：
--
作者：
Chomel JC;Bonnet ML;Sorel N;Sloma I;Bennaceur-Griscelli A;Rea D;Legros L;Marfaing-Koka A;Bourhis JH;Ame S;Guerci-Bresler A;Rousselot P;Turhan AG
通讯作者：
Turhan AG
影响因子：
11.4
作者：
Hughes TP;Saglio G;Quintás-Cardama A;Mauro MJ;Kim DW;Lipton JH;Bradley-Garelik MB;Ukropec J;Hochhaus A
通讯作者：
Hochhaus A