Abstract
Incomplete abolition of tumorigenicity creates potential safety concerns in clinical trials of regenerative medicine based on human pluripotent stem cells (hPSCs). Here, we demonstrate that conditionally replicating adenoviruses that specifically target cancers using multiple factors (m-CRAs), originally developed as anticancer drugs, may also be useful as novel antitumorigenic agents in hPSC-based therapy. The survivin promoter was more active in undifferentiated hPSCs than the telomerase reverse transcriptase (TERT) promoter, whereas both promoters were minimally active in differentiated normal cells. Accordingly, survivin-responsive m-CRA (Surv.m-CRA) killed undifferentiated hPSCs more efficiently than TERT-responsive m-CRAs (Tert.m-CRA); both m-CRAs exhibited efficient viral replication and cytotoxicity in undifferentiated hPSCs, but not in cocultured differentiated normal cells. Pre-infection of hPSCs with Surv.m-CRA or Tert.m-CRA abolished in vivo teratoma formation in a dose-dependent manner following hPSC implantation into mice. Thus, m-CRAs, and in particular Surv.m-CRAs, represent novel antitumorigenic agents that could facilitate safe clinical applications of hPSC-based regenerative medicine.
Highlights
Human pluripotent stem cells, including human embryonic stem cells and human-induced pluripotent stem cells, are promising sources of material for use in cell transplantation therapy
Survivin and telomerase reverse transcriptase (TERT) mRNAs were expressed at high levels in undifferentiated human embryonic stem cells (hESCs) and iPSCs relative to differentiated cells, as well as in PC3 cancer cells relative to normal human dermal fibroblasts (HDFs); a low level of survivin mRNA expression was detected in normal HDFs and differentiated human-induced pluripotent stem cells (hiPSCs) (Figure 1a–c)
We investigated whether Surv.m-Conditionally replicating adenoviruses (CRAs) and Tert.multiple cancer-specific factors (m-CRAs) exerted efficient and undifferentiated cell-specific viral replication and cytotoxicity in Human pluripotent stem cells (hPSCs), relative to two control groups infected with replication-deficient adenoviral vector ubiquitously expressing enhanced green fluorescent protein (EGFP) (Ad.CA-EGFP) or no transgenic protein (Figures 2 and 3)
Summary
Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs), are promising sources of material for use in cell transplantation therapy. The risk of formation of tumors, including teratomas and cancers originating from contaminating undifferentiated and transformed cells, represents the most critical obstacle to the safe clinical application of hPSC-based regenerative medicine.[1] Multiple approaches have been taken to improve safety by reducing the risk of carcinogenesis. Innovative safety approaches should be developed in order to decrease this risk
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