Clinical Medicine Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.
Int J Mol Sci. 2020 May 5;21(9):3265. doi: 10.3390/ijms21093265.
Induced pluripotent stem cells (iPSCs) are regarded as a promising option for cell-based regenerative medicine. To obtain safe and efficient iPSC-based cell products, it is necessary to selectively eliminate the residual iPSCs prior to in vivo implantation due to the risk of teratoma formation. Bee venom (BV) has long been used in traditional Chinese medicine to treat inflammatory diseases and relieve pain, and has been shown to exhibit anti-cancer, anti-mutagenic, anti-nociceptive, and radioprotective activities. However, the potential benefits of BV in iPSC therapy, particularly its anti-teratoma activity, have not been examined. In this study, we found that BV selectively induced cell death in iPSCs, but not in iPSC-derived differentiated cells (iPSCs-Diff). BV rapidly disrupted cell membrane integrity and focal adhesions, followed by induction of apoptosis and necroptosis in iPSCs. We also found that BV remarkably enhanced intracellular calcium levels, calpain activation, and reactive oxygen speciesgeneration in iPSCs. BV treatment before in ovo grafting efficiently prevented iPSC-derived teratoma formation. In contrast, no DNA damage was observed in iPSCs-Diff following BV treatment, further demonstrating the safety of BV for use with iPSCs-Diff. Taken together, these findings show that BV has potent anti-teratoma activity by eliminating residual iPSCs, and can be used for the development of effective and safe iPSC-based cell therapies.
诱导多能干细胞（iPSCs）被认为是细胞再生医学的一种很有前途的选择。为了获得安全有效的基于 iPSC 的细胞产品，有必要在体内植入前选择性地消除残留的 iPSC，因为存在形成畸胎瘤的风险。蜂毒（BV）长期以来一直被用于中药治疗炎症性疾病和缓解疼痛，并且已显示出具有抗癌、抗突变、抗伤害感受和放射保护活性。然而，BV 在 iPSC 治疗中的潜在益处，特别是其抗畸胎瘤活性，尚未得到检验。在这项研究中，我们发现 BV 选择性地诱导 iPSCs 死亡，而不诱导 iPSC 衍生的分化细胞（iPSCs-Diff）死亡。BV 迅速破坏细胞膜完整性和焦点粘连，随后诱导 iPSCs 凋亡和坏死。我们还发现，BV 显著增加了 iPSCs 中的细胞内钙水平、钙蛋白酶激活和活性氧生成。在鸡胚移植前进行 BV 处理可有效地防止 iPSC 衍生的畸胎瘤形成。相比之下，BV 处理后在 iPSCs-Diff 中未观察到 DNA 损伤，进一步证明了 BV 对 iPSCs-Diff 的安全性。总之，这些发现表明，BV 通过消除残留的 iPSC 具有强大的抗畸胎瘤活性，可用于开发有效和安全的基于 iPSC 的细胞疗法。
