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人脐带间充质干细胞递送的可溶性肿瘤坏死因子相关凋亡诱导配体在体内外抑制B淋巴细胞白血病细胞增殖并促进其凋亡。

Human Umbilical Cord MSC Delivered-Soluble TRAIL Inhibits the Proliferation and Promotes Apoptosis of B-ALL Cell In Vitro and In Vivo.

作者信息

Chen Fangshan, Zhong Xianmei, Dai Qian, Li Kuo, Zhang Wei, Wang Jie, Zhao Yueshui, Shen Jing, Xiao Zhangang, Xing Hongyun, Li Jing

机构信息

Department of Oncology and Hematology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou 646000, China.

Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China.

出版信息

Pharmaceuticals (Basel). 2022 Nov 11;15(11):1391. doi: 10.3390/ph15111391.

DOI:10.3390/ph15111391
PMID:36422522
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9693801/
Abstract

The TNF-related apoptosis-inducing ligand (TRAIL) could induce apoptosis of leukemic cells, while showed no cytotoxic effect on normal cells. One of the limitations for application of recombinant TRAIL (rhTRAIL) in leukemia treatment is that the serum half-life of this protein is short. Gene delivery is a good strategy to prolong the half-life of TRAIL. In this study, we genetically engineered umbilical cord-MSCs to continuously express and secrete soluble TRAIL (MSC-sTRAIL), to investigate the effects of MSC-sTRAIL on B-cell acute lymphocytic leukemia (B-ALL) cells. In vitro, MSC-sTRAIL significantly inhibited the proliferation of B-ALL cells by suppressing PI3K/AKT and MEK/ERK signaling pathways, and induced apoptosis of B-ALL cells via the caspase cascade-mediated pathway and mitochondrial-mediated pathway. In vivo, MSC-sTRAIL dramatically inhibited B-ALL cell growth. Meanwhile, B-ALL-induced splenic and renal injuries were significantly alleviated after MSC-sTRAIL treatment. Moreover, the serum levels of MSC-secreted sTRAIL were still high in MSC-sTRAIL treated mice, indicating an extended half-life of sTRAIL. Our study suggests that MSC delivered-TRAIL secretion is a potential therapeutic strategy for B-ALL treatment.

摘要

肿瘤坏死因子相关凋亡诱导配体（TRAIL）可诱导白血病细胞凋亡，而对正常细胞无细胞毒性作用。重组TRAIL（rhTRAIL）在白血病治疗应用中的局限性之一是该蛋白的血清半衰期较短。基因递送是延长TRAIL半衰期的一种良好策略。在本研究中，我们对脐带间充质干细胞进行基因工程改造，使其持续表达并分泌可溶性TRAIL（MSC-sTRAIL），以研究MSC-sTRAIL对B细胞急性淋巴细胞白血病（B-ALL）细胞的影响。在体外，MSC-sTRAIL通过抑制PI3K/AKT和MEK/ERK信号通路显著抑制B-ALL细胞的增殖，并通过半胱天冬酶级联介导的途径和线粒体介导的途径诱导B-ALL细胞凋亡。在体内，MSC-sTRAIL显著抑制B-ALL细胞生长。同时，MSC-sTRAIL治疗后，B-ALL诱导的脾脏和肾脏损伤得到显著缓解。此外，在接受MSC-sTRAIL治疗的小鼠中，MSC分泌的sTRAIL血清水平仍然很高，表明sTRAIL的半衰期延长。我们的研究表明，间充质干细胞递送TRAIL分泌是一种潜在的B-ALL治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd19/9693801/7be8762e24d2/pharmaceuticals-15-01391-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd19/9693801/75e70a40af57/pharmaceuticals-15-01391-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd19/9693801/a0c569dcf1be/pharmaceuticals-15-01391-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd19/9693801/51c3ded8818b/pharmaceuticals-15-01391-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd19/9693801/7be8762e24d2/pharmaceuticals-15-01391-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd19/9693801/75e70a40af57/pharmaceuticals-15-01391-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd19/9693801/a0c569dcf1be/pharmaceuticals-15-01391-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd19/9693801/51c3ded8818b/pharmaceuticals-15-01391-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cd19/9693801/7be8762e24d2/pharmaceuticals-15-01391-g004.jpg

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