Ischemia, Immunosuppression, and SSEA-1-Negative Cells All Contribute to Tumors Resulting From Mouse Embryonic Stem Cell-Derived Neural Progenitor Transplantation
Ischemia, Immunosuppression, and SSEA-1-Negative Cells All Contribute to Tumors Resulting From Mouse Embryonic Stem Cell-Derived Neural Progenitor Transplantation
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缺血、免疫抑制和 SSEA-1 阴性细胞均导致小鼠胚胎干细胞来源的神经祖细胞移植产生肿瘤
DOI：
10.1002/jnr.23292
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发表时间：
2014-01-01
影响因子：
4.2
通讯作者：
Zhang, Y. Alex
中科院分区：
文献类型：
--
作者：
Guan, Yunqian;Zou, Haiqiang;Zhang, Y. Alex
来源于小鼠胚胎干细胞的神经前体细胞移植后可导致肿瘤的发生。这种肿瘤的细胞来源仍然存在争议。我们在大鼠中风模型和裸鼠中研究了由mES细胞衍生的NPC引起的肿瘤形成。缺血2小时再灌注48小时后，将NPC移植到异种大鼠的缺血核心中。移植后4周，发现移植的细胞在坏死的边界处存活，并已分化为神经元。移植的大鼠没有表现出任何行为改善，因为90%的动物形成了肿瘤。免疫抑制促进肿瘤形成。NPC移植后，给予环孢素A后，40%的正常大鼠出现肿瘤。同时，在没有环孢菌素A的情况下没有观察到肿瘤形成。缺血性损伤也促进了肿瘤的形成，因为NPC在90%的缺血大鼠中产生了肿瘤，这一百分比显著高于完整大鼠的40%。从第4阶段分离的SSEA-1阳性细胞不是完全未分化的ES细胞。它们表现出与ES细胞不同的标记基因转录谱，并且在移植的裸鼠中不形成肿瘤。分化后残留的未分化ES细胞也不会导致肿瘤。首先，正常大鼠脑中未分化的ES细胞的肿瘤形成率为0%，显著低于NPC。第二，移植的NPC在裸鼠中导致100%的肿瘤，含有约1.5 × 10（3）Oct-4阳性细胞;然而，即使是5 × 10（5）未分化的ES细胞也仅在40%的裸鼠中形成肿瘤。(c)2013 Wiley Periodicals，Inc.
Neural progenitor cells (NPCs) derived from mouse embryonic stem (mES) cells can lead to tumors after transplantation. The cellular source of such tumors remains under debate. We investigated the tumor formation resulting from mES cell-derived NPCs in a rat stroke model and in nude mice. After 2 hr of ischemia and 48 hr of reperfusion, the NPCs were transplanted into the ischemic core of the xenogeneic rats. Four weeks after transplantation, the grafted cells were found to be viable at the border of the necrosis and had differentiated into neurons. Transplanted rats did not exhibit any behavioral improvement, because tumor formed in 90% of the animals. Immunosuppression facilitated tumor formation. Tumors were observed in 40% of normal rats after NPC transplantation when cyclosporin A was administered. Meanwhile, no tumor formation was observed without cyclosporin A. Ischemic damage also facilitated tumor formation, because NPCs gave rise to tumors in 90% of ischemic rats, a percentage significantly higher than that in intact rats, which was 40%. The SSEA-1-positive cells isolated from stage 4 are not exactly undifferentiated ES cells. They exhibited a marker gene transcription profile different from that of ES cells and did not form tumors in transplanted nude mice. The undifferentiated ES cells remaining after differentiation did not contribute to tumors either. First, the tumor formation rate resulting from undifferentiated ES cells in the brains of normal rats is 0%, significantly lower than that of NPCs. Second, transplanted NPCs that led to 100% tumors in nude mice contained approximately 1.5 x 10(3) Oct-4-positive cells; however, even 5 x 10(5) undifferentiated ES cells formed neoplasm only in 40% nude mice. (c) 2013 Wiley Periodicals, Inc.