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Abstract：
The extrapolability of the current tumorigenicity test performed by transplanting human cell product into immunodeficient (NOG) mice was investigated. For this purpose, the susceptibility to form teratomas of NOG mice was assessed by transplanting undifferentiated human-induced pluripotent stem cells (hiPSCs) as positive control cells via the liver, striatum, or tail vein and evaluating the TPD50 value (dose required to form teratomas in half of the transplanted mice). This was then compared to the TPD50 of syngeneic or allogeneic mouse models. The TPD50 of C57/BL/6(B6)-iPSC or 129/Ola(129)-embryonic stem cell (ESC) transplanted into the liver of syngeneic mice was 4.08 × 105 and 4.64 × 104 cells, respectively, while the TPD50 of hiPSC administered into the liver of NOG mice was 4.64 × 104 cells. The TPD50 of B6-miPSC-synergic, 129-mESC-synergic, or 129-cell/B6 allogeneic transplantation into the striatum was 5.09 × 102, 1.0 × 104, and 3.73 × 104 cells, respectively, while that of hiPSC/NOG mice was 1.0 × 103 cells. The TPD50 for B6-miPSC or 129-mESC syngeneic tail vein infusion was 3.16 × 106 or 5.62 × 106 cells, respectively, while no incidence was observed from 1 × 107 B6-miPSCs in 129 mice or hiPSCs in NOG mice infusion study. Although the number of data sets was limited, these data indicate that the teratoma formation from transplanted undifferentiated hiPSCs via the liver or striatum in NOG mice is comparable to that in syngeneic or allogeneic mouse transplantation model, suggesting that the result of the current tumorigenicity test in NOG mice would provide useful information to infer the incidence of teratoma from residual undifferentiated hPSCs in hPSC-derived products after transplantation.
摘要：
研究了通过将人细胞产物移植到免疫缺陷（NOG）小鼠中进行的当前致瘤性测试的外推性。为此,通过肝脏移植未分化的人诱导多能干细胞（hiPSCs）作为阳性对照细胞来评估NOG小鼠对畸胎瘤的易感性，纹状体,或尾静脉并评估TPD50值（在一半的移植小鼠中形成畸胎瘤所需的剂量）。然后将其与同基因或同种异体小鼠模型的TPD50进行比较。C57/BL/6(B6)-iPSC或129/Ola(129)-胚胎干细胞(ESC)移植入同系小鼠肝脏的TPD50分别为4.08×105和4.64×104,分别,而对NOG小鼠肝脏给予hiPSC的TPD50为4.64×104个细胞。B6-miPSC协同剂的TPD50，129-mESC-协同，或129细胞/B6同种异体移植入纹状体的细胞为5.09×102、1.0×104和3.73×104细胞，分别,而hiPSC/NOG小鼠为1.0×103个细胞。B6-miPSC或129-mESC同系尾静脉输注的TPD50为3.16×106或5.62×106细胞，分别,而129只小鼠中的1×107个B6-miPSC或NOG小鼠输注研究中的hiPSC未观察到发生率。尽管数据集的数量有限，这些数据表明，NOG小鼠通过肝脏或纹状体移植的未分化hiPSCs形成的畸胎瘤与同系或同种异体小鼠移植模型相当，提示当前NOG小鼠致瘤性测试的结果将提供有用的信息，以推断移植后hPSC衍生产品中残留的未分化hPSC的畸胎瘤发生率。
