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Abstract
Small molecules to selectively induce cell death of undifferentiated human pluripotent stem cells (hPSCs) have been developed with the aim of lowering the risk of teratoma formation during hPSC-based cell therapy. In this context, we have reported that Quercetin (QC) induces cell death selectively in hESCs via p53 mitochondrial localization. However, the detailed molecular mechanism by which hESCs undergo selective cell death induced by QC remains unclear.Herein, we demonstrate that mitochondrial reactive oxygen species (ROS), strongly induced by QC in human embryonic stem cells (hESCs) but not in human dermal fibroblasts (hDFs), were responsible for QC-mediated hESC’s cell death. Increased p53 protein stability and subsequent mitochondrial localization by QC treatment triggered mitochondrial cell death only in hESCs. Of interest, peptidylprolyl isomerase D [PPID, also called cyclophilin D (CypD)], which functions in mitochondrial permeability transition and mitochondrial cell death, was highly expressed in hESCs. Inhibition of CypD by cyclosporine A (CsA) clearly inhibited the QC-mediated loss of mitochondrial membrane potential and mitochondrial cell death. These results suggest that p53 and CypD in the mitochondria are critical for the QC-mediated induction of cell death in hESCs.
Highlights
Risk of teratoma formation from residual undifferentiated pluripotent stem cells (PSCs), due to high telomerase activity and active proliferation, has been considered to be one of the major roadblocks to the clinical application of human pluripotent stem cells (hPSCs) in cell therapy [1]
Given that QC acts either as a pro-oxidant to be cytotoxic to cancer cells with active proliferation [8, 10] or as an anti-oxidant [9], depending on the cell models, we surmised that QC may serve as a pro-oxidant to produce reactive oxygen species (ROS) in human embryonic stem cells (hESCs), which undergo active proliferation similar to that in cancer cells
We first compared the level of ROS in hESCs with that in human dermal fibroblasts (hDFs), which were used as a model for differentiated cells and which are highly resistant to QC-induced cell death (Figure 1A)
Summary
Risk of teratoma formation from residual undifferentiated pluripotent stem cells (PSCs), due to high telomerase activity and active proliferation, has been considered to be one of the major roadblocks to the clinical application of hPSCs in cell therapy [1]. To resolve this problem, numerous attempts to selectively eliminate undifferentiated hPSCs, have been examined, including integration of suicide genes [2, 3], immunodepletion using antibodies [4], and selective induction of cell death using small molecules [5, 6]. It is noteworthy that a set of anti-oxidants whose expression is regulated by p53 after oxidative stress [16], failed to be increased in murine ESCs during stress conditions, causing mitochondrial cell death due to mitochondrial localization of p53 [14]
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