Natural Killer Cells Prevent the Formation of Teratomas Derived From Human Induced Pluripotent Stem Cells
Natural Killer Cells Prevent the Formation of Teratomas Derived From Human Induced Pluripotent Stem Cells
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DOI：
10.3389/fimmu.2019.02580
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发表时间：
2019-11-07
影响因子：
7.3
通讯作者：
Beausejour, Christian
中科院分区：
文献类型：
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作者：
Benabdallah, Basma;Desaulniers-Langevin, Cynthia;Beausejour, Christian
诱导多能干细胞（iPSC）衍生物在临床使用的安全性归因于完全消除了移植后形成畸胎瘤的风险。这种风险在免疫能力强的宿主中存在的程度目前尚不清楚。在这里，我们使用胎儿造血干细胞和自体胸腺组织重建的人源化小鼠（骨-肝-胸腺人源化小鼠[Hu-BLT]）或继外周血单核细胞（PBMC）（Hu-AT）过继移植后，评估了免疫细胞预防或消除源自人类iPSC（hiPSC）的畸胎瘤的能力。我们的结果表明，注射 hiPSC 未能在用同种异体或自体 PBMC 或单独纯化的自然杀伤 (NK) 细胞重建的 Hu-AT 小鼠中形成畸胎瘤。然而，在用去除 NK 细胞的自体 PBMC 重建的 Hu-AT 小鼠中观察到畸胎瘤。与这些结果一致，Hu-BLT 不具有功能性 NK 细胞，无法阻止畸胎瘤的生长。最后，我们发现 Hu-AT 小鼠中已形成的畸胎瘤不被 NK 细胞靶向，而是被同种异体而非自体 T 细胞有效排斥。总体而言，我们的研究结果表明，自体 hiPSC 衍生疗法在 NK 细胞存在的情况下不太可能形成畸胎瘤。
The safe utilization of induced pluripotent stem cell (iPSC) derivatives in clinical use is attributed to the complete elimination of the risk of forming teratomas after transplantation. The extent by which such a risk exists in immune-competent hosts is mostly unknown. Here, using humanized mice reconstituted with fetal hematopoietic stem cells and autologous thymus tissue (bone-liver-thymus humanized mice [Hu-BLT]) or following the adoptive transfer of peripheral blood mononuclear cells(PBMCs) (Hu-AT), we evaluated the capacity of immune cells to prevent or eliminate teratomas derived from human iPSCs (hiPSCs). Our results showed that the injection of hiPSCs failed to form teratomas in Hu-AT mice reconstituted with allogeneic or autologous PBMCs or purified natural killer (NK) cells alone. However, teratomas were observed in Hu-AT mice reconstituted with autologous PBMCs depleted from NK cells. In line with these results, Hu-BLT, which do not have functional NK cells, could not prevent the growth of teratomas. Finally, we found that established teratomas were not targeted by NK cells and instead were efficiently rejected by allogeneic but not autologous T cells in Hu-AT mice. Overall, our findings suggest that autologous hiPSC-derived therapies are unlikely to form teratomas in the presence of NK cells.