Direct in vivo application of induced pluripotent stem cells is feasible and can be safe
Direct in vivo application of induced pluripotent stem cells is feasible and can be safe
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诱导多能干细胞的直接体内应用是可行且安全的
DOI：
10.7150/thno.28671
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Chen, Sifeng
中科院分区：
文献类型：
--
作者：
Xiang, Meng;Lu, Meng;Chen, Sifeng
越来越多的证据表明，直接在体内应用诱导多能干细胞(IPSCs)是不可行的共识可能不是真的。方法：对53例脑、肺、肝、肾、胰岛、皮肤、后肢和动脉的正常和疾病状态下的畸胎瘤的形成和转归进行研究。结果：采用经典的畸胎瘤发生试验，要求IPSCs聚集和限制，所有受试的小鼠、人和个性化的自体猴子IPSCs都形成畸胎瘤，而IPSC来源的细胞没有形成畸胎瘤。静脉或局部传播的IPSC不会形成畸胎瘤，剂量高达2.5×108 IPSCs/kg，观察时间长达18个月，无论宿主组织类型；自体、同基因或免疫缺陷宿主动物；是否有疾病；疾病类型；IPSC诱导方法；商业或自我诱导的IPSCs；小鼠、人或猴子IPSCs；分娩频率；性别。Matrigel受限的，但不是PBS悬浮的，同基因的ipscs被输送到腹膜或肾包膜形成畸胎瘤。静脉注射IPSCs治疗剂量低至5×106/kg，部分IPSCs在损伤器官中分化为体细胞。播散性IPSCs进入受损组织，在受损器官中的存活时间明显长于未受伤的器官。在没有疾病的动物中，静脉注射的细胞没有分化成不需要的长期细胞，或者作为静止的干细胞存活下来。在共培养中，干细胞培养液和优势细胞类型是IPSCs形成细胞团的关键。结论：通过细胞扩散可以很容易地完全避免畸胎瘤的发生。体内直接应用IPSC是可行的，也是安全的。
Increasing evidence suggests the consensus that direct in vivo application of induced pluripotent stem cells (iPSCs) is infeasible may not be true. Methods: Teratoma formation and fate were examined in 53 normal and disease conditions involving brain, lung, liver, kidney, islet, skin, hind limb, and arteries. Results: Using classic teratoma generation assays, which require iPSCs to be congregated and confined, all mouse, human, and individualized autologous monkey iPSCs tested formed teratoma, while iPSC-derived cells did not. Intravenously or topically-disseminated iPSCs did not form teratomas with doses up to 2.5×108 iPSCs/kg and observation times up to 18 months, regardless of host tissue type; autologous, syngeneic, or immune-deficient host animals; presence or absence of disease; disease type; iPSC induction method; commercial or self-induced iPSCs; mouse, human, or monkey iPSCs; frequency of delivery; and sex. Matrigel-confined, but not PBS-suspended, syngeneic iPSCs delivered into the peritoneal cavity or renal capsule formed teratomas. Intravenously administered iPSCs were therapeutic with a dose as low as 5×106/kg and some iPSCs differentiated into somatic cells in injured organs. Disseminated iPSCs trafficked into injured tissue and survived significantly longer in injured than uninjured organs. In disease-free animals, no intravenously administered cell differentiated into an unwanted long-lasting cell or survived as a quiescent stem cell. In coculture, the stem cell medium and dominant cell-type status were critical for iPSCs to form cell masses. Conclusion: Teratoma can be easily and completely avoided by disseminating the cells. Direct in vivo iPSC application is feasible and can be safe.