The tumourigenicity of iPS cells and their differentiated derivates

Authors

  • Zhiqiang Liu,

    1. Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, China
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    • The first three authors contributed equally to this work.
  • Yu Tang,

    1. Department of Ultrasound, PLA 302 Hospital, Beijing, China
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    • The first three authors contributed equally to this work.
  • Shuanghong Lü,

    1. Laboratory of Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
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    • The first three authors contributed equally to this work.
  • Jin Zhou,

    1. Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, China
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  • Zhiyan Du,

    1. Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, China
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  • Cuimi Duan,

    1. Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, China
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  • Zhiyan Li,

    Corresponding author
    1. Department of Ultrasound, PLA 302 Hospital, Beijing, China
    • Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, China
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  • Changyong Wang

    Corresponding author
    • Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical Sciences, Beijing, China
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Correspondence to: Changyong WANG, M.D., Ph.D., Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences and Tissue Engineering Research Center, Academy of Military Medical Sciences, 27 Taiping Rd, Beijing 100850, China.

Tel.: 8610-68166874

Fax: 8610-68166874

E-mail: wcy2000_te@yahoo.com

Zhiyan LI, Department of Ultrasound, PLA 302 Hospital, Beijing 100039, China.

Tel./Fax: 8610-63833268

E-mail: lzyyuer@sina.com

Abstract

Induced pluripotent stem cell (iPSC) provides a promising seeding cell for regenerative medicine. However, iPSC has the potential to form teratomas after transplantation. Therefore, it is necessary to evaluate the tumorigenic risks of iPSC and all its differentiated derivates prior to use in a clinical setting. Here, murine iPSCs were transduced with dual reporter gene consisting of monomeric red fluorescent protein (mRFP) and firefly luciferase (Fluc). Undifferentiated iPSCs, iPSC derivates from induced differentiation (iPSC-derivates), iPSC-derivated cardiomyocyte (iPSC-CMs) were subcutaneously injected into the back of nude mice. Non-invasive bioluminescence imaging (BLI) was longitudinally performed at day 1, 7, 14 and 28 after transplantation to track the survival and proliferation of transplanted cells. At day 28, mice were killed and grafts were explanted to detect teratoma formation. The results demonstrated that transplanted iPSCs, iPSC-derivates and iPSC-CMs survived in receipts. Both iPSCs and iPSC-derivates proliferated dramatically after transplantation, while only slight increase in BLI signals was observed in iPSC-CM transplanted mice. At day 28, teratomas were detected in both iPSCs and iPSC-derivates transplanted mice, but not in iPSC-CM transplanted ones. In vitro study showed the long-term existence of pluripotent cells during iPSC differentiation. Furthermore, when these cells were passaged in feeder layers as undifferentiated iPSCs, they would recover iPSC-like colonies, indicating the cause for differentiated iPSC's tumourigenicity. Our study indicates that exclusion of tumorigenic cells by screening in addition to lineage-specific differentiation is necessary prior to therapeutic use of iPSCs.

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