利用改造的间充质干细胞外泌体装载miR-34c-5p靶向诱导急性髓系白血病干细胞衰老与清除的研究

Leukemia stem cells (LSCs) are one of the main causes for recurrence and drug resistance in acute myeloid leukemia (AML). Previous studies have confirmed that miR-34c-5p can induce LSCs senescence and promote the clearance of AML cells in mice. In order to transfer miR-34c-5p to bone marrow and induce LSCs senescence without affecting normal cells, this study is intended to use the modified exosomes derived from mesenchymal stem cells (MSCs) as a carrier of transporting miR-34c-5p to bone marrow to target LSCs. First, the lamp2b-IL3-eGFP plasmid is transfected into MSCs, so that the IL3 expressed on exosomes can combine with the specific molecular (CD123, also named IL-3 receptor) on the surface of LSCs. To enhance its ability of homing to bone marrow, CD44 molecule expressed on exosomes is glycosylated and transformed into hematopoietic cell E-selectin/L-selectin Ligand (HCELL). Then, miR-34c-5p is electric transfected into the modified exosomes and carried to bone marrow to induce LSCs senescence and clearance. The completion of this project is expected to construct a new-type exosomes carrier loading with miR-34c-5p or other molecular to targeted treat AML.

白血病干细胞（LSCs）是急性髓系白血病（AML）复发与耐药的根源，前期研究证实miR-34c-5p能诱导LSCs衰老并促进小鼠体内AML干细胞的清除。然而，miR-34c-5p也可能诱导正常细胞衰老。为使miR-34c-5p靶向传递至骨髓诱导LSCs衰老而不影响正常细胞，本研究拟以改造的间充质干细胞外泌体为miR-34c-5p载体。首先通过转染lamp2b-IL3-eGFP融合质粒使间充质干细胞外泌体膜表达LSCs表面特异性分子CD123受体（白介素-3），而后利用岩藻糖基化处理使外泌体膜表面CD44分子转化成骨髓归巢能力更强的HCELL分子，最后通过电转染技术将miR-34c-5p导入到改造后的MSC外泌体内，并观察其靶向重启LSCs衰老与清除的能力。本项目的完成有望构建装载miR-34c-5p或其他目标分子并靶向治疗AML的新型外泌体载体。

白血病干细胞(LSCs)是急性髓系白血病( AML)复发与耐药的根源，前期研究证实miR -34c-5p能诱导LSCs衰老并促进小鼠体内AML干细胞的清除。然而，miR-34c-5p 在血液循环运输中极易被 RNA 酶降解，且可能诱导某些低表达 miR-34c-5p 的正常体细胞衰老;此外，还难以作用于隐匿在骨髓壁龛内的 LSCs为使miR-34c-5p靶向传递至骨髓诱导LSCs衰老而不影响正常造血细胞，本研究以间充质干细胞外泌体为载体，通过转染lamp2b-IL3-eGFP融合质粒使间充质干细胞外泌体膜表达LSCs表面特异性分子CD123受体(白介素-3)，而后利用岩藻糖基化处理使外泌体 膜表面CD44分子转化成骨髓归巢能力更强的分子HCELL，最后通过电转染方法将miR-34c-5p转 染至改造后的MSC外泌体内，并观察其靶向重启LSCs衰老与清除的能力。本项目成功构建了装载miR-34c-5p或其他目标分子并靶向治疗AML的新型外泌体载体。

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