The Review by Behfar and colleagues (Cell therapy for cardiac repair—lessons from clinical trials. Nat. Rev. Cardiol. 11, 232–246; 2014)1 summarized that 'first-generation' cell therapies for heart failure2 using autologous cells are safe for use in humans. Conversely, 'next-generation' cell therapies, which include pluripotent stem cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have major safety concerns, because contamination of undifferentiated cells might lead to teratoma formation.3 However, novel and efficient protocols for selective shutdown of tumour formation in these cells have been reported in several studies, which merit discussion (Table 1).

Table 1 Novel strategies for selective elimination of teratoma
Full size table

Firstly, chemical inhibitors of survivin potently induce selective and complete cell death of undifferentiated human ESCs or iPSCs.4,5 A single pretreatment exposure to survivin inhibitors is sufficient to completely inhibit teratoma formation after transplantation.4 Importantly, differentiated cells derived from human ESCs or iPSCs maintain their functionality after treatment with survivin inhibitors.4 The survivin inhibitor QC has been widely used as nutritional supplement and no adverse effects have been reported.4 Secondly, chemical inhibitors of oleate synthesis have been identified as compounds for selective elimination of human ESCs or iPSCs.6,7 Oleate synthesis inhibitors lead to apoptosis in human ESCs or iPSCs through lipid metabolism, revealing a dependence of these cells on oleate. At present, application of oleate synthesis inhibitors is limited to in vitro culture before transplantation; whether these inhibitors might be applied in vivo remains to be determined. Thirdly, the diabetes mellitus drug metformin8 can reduce tumour forming potential of iPSCs without affecting pluripotency;9 however, in this study only mouse iPSCs were investigated. Metformin, an agonist of AMP-activated protein kinase, suppresses the expression of Oct4 and survivin thereby showing previously unrecognized stem-cell toxicity.10 Finally, an antibody against stage-specific embryonic antigen-5 (a newly identified PSC-specific surface antigen) can be used to remove undifferentiated cells by fluorescence-activated cell sorting.11 However, because this method depends on cell sorting, which includes ex vivo manipulation (such as single-cell dissociation and cell-staining techniques), cells might lose viability. New synthesized small molecules (such as JC011), which selectively induce a cytotoxic endoplasmic reticulum stress response in ESCs and iPSCs, have also been reported, but further studies should reveal the precise mechanisms of this pathway.12

We believe that two issues relating to the use of ESC or iPSC therapies need to be addressed. After treating cells with chemical inhibitors to prevent teratoma, these cells should be tested to ensure that they have maintained functional properties, including differentiation capacity13 and engraftment potential. Efficiency, as well as safety, is required for ideal cell transplantation. A second problem is that malignant cell transformation, other than teratoma formation, after transplantation of PSC-derived cells might also exist. Pluripotent tumour forming potential can be divided into two categories: malignant transformation of differentiated PSCs, and benign teratoma formation from residual undifferentiated PSCs.14,15 The former should be also investigated for safety. For example, CD30, which is a biomarker for transformed human ESCs, is correlated with karyotype abnormalities such as partial duplication of chromosome.16 Further elucidation of this issue is needed before a judgement on iPSC clinical safety can be made.