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Abstract
We herein report a novel mechanism of action of statin preparations using a new drug discovery method. Milk fat globule-EGF factor 8 protein (MFG-E8) was identified from the secretory component of mouse embryonic fibroblast (MEF) as a cell adhesion-promoting factor effective for screening active cellular agents of human induced pluripotent stem cells (hiPSCs) in vitro using electrochemical impedance. Our analyses showed that atorvastatin did not cause death in myocardial cells differentiated from hiPSCs but reduced the pluripotent cell survival in vitro when using serum- and albumin-free media, and inhibited the ability to form teratomas in mice. This result could have been already the cytopathic effect of atorvastatin, and complete elimination of hiPSCs was confirmed in the xenotransplantation assay. The administration of atorvastatin to hiPSCs caused the expression of hypoxia inducible factor (HIF)1α mRNA to be unchanged at 6 hr and downregulated at 24 hr. In addition, the inhibition of the survival of hiPSCs was confirmed by HIF1α-peroxisome proliferator-activated receptor (PPAR) axis inhibition. These results suggest that the addition of atorvastatin to hiPSC cultures reduces the survival of pluripotent cells by suppressing the HIF1α-PPAR axis. In summary, the HIF1α-PPAR axis has an important role in maintaining the survival of pluripotent hiPSCs.
Highlights
The persistence of pluripotent cells in cell-based medicinal products derived from human induced pluripotent stem cells[1,2] is a potential risk for oncogenesis after transplantation into patients.[3,4] hPSCs have two unique properties: self-renewal, which is the ability to proliferate indefinitely while maintaining their cellular identity; and pluripotency, which is the ability to differentiate into all cell types that comprise the embryo proper
Several strategies have been suggested for the removal of residual pluripotent cells from differentiated cultures: cell sorting of hPSCs using immunological targeting based on specific antigens for pluripo
We showed that the ROCK inhibitor (Y-27632) could not rescue human induced pluripotent stem cells (hiPSCs) from the survival-suppressing effect of atorvastatin (Figure 2F) and fluvastatin (Figure 2I)
Summary
The persistence of pluripotent cells in cell-based medicinal products derived from human induced pluripotent stem cells (hiPSCs)[1,2] is a potential risk for oncogenesis after transplantation into patients.[3,4] hPSCs have two unique properties: self-renewal, which is the ability to proliferate indefinitely while maintaining their cellular identity; and pluripotency, which is the ability to differentiate into all cell types that comprise the embryo proper These traits make hPSCs promising for future application in regenerative medicine;[5] these same traits make them potentially tumorigenic[6,7] and currently hinder the fulfillment of their clinical potential.[4] The specific problem associated with the medical use of cells differentiated from cultured hPSCs is the concern that some may not have completed differentiation. In light of the widespread effects and consequences of statin treatments described above, the present study was performed to determine whether or not statins might be an effective means of removing residual undifferentiated hPSCs from cell cultures
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