Limits...
Eliminating residual iPS cells for safety in clinical application.

Masuda S, Miyagawa S, Fukushima S, Sougawa N, Okimoto K, Tada C, Saito A, Sawa Y - Protein Cell (2015)

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

First-in-human clinical trial for age-related macular degeneration using iPSC-derived retinal pigment epithelium (RPE) cells was conducted in 2014, showing no serious adverse effects to date, including tumor formation... However, in the case of clinical trial using iPSC-derived cardiomyocytes, 10–10 cells would be required for transplantation; strict control of residual undifferentiated cells should be necessary for safer clinical application... Previously, Tateno and colleagues discovered that a lectin, called rBC2LCN, binds to human iPSCs and embryonic stem cells (ESCs), but not to differentiated cells (Tateno et al. )... Notably, lectin-toxin fusion protein (rBC2LCN-PE23) could bind to and successfully be internalized by human iPSCs, suggesting that lectin (rBC2LCN) could be useful for delivery of cytotoxic agents into human iPSCs... Furthermore, within 24 h, complete elimination of human iPSCs was achieved by culture in the presence of lectin-toxin fusion protein, indicating that rBC2LCN-PE23 exerts a robust cytotoxic effect on human iPSCs... On the other hand, it has a negligible cytotoxic effect on differentiated cells, thereby enabling selective elimination of human iPSCs in a mixed cell population (Tateno et al. )... In the present study by Tateno and colleagues, although selective elimination of human iPSCs was examined in a mixed cell population (where human fibroblasts were spiked by human iPSCs) (Tateno et al. ), differentiated cells (derived from human iPSCs) containing undifferentiated cells should be examined precisely in the future... The authors demonstrated that purvalanol A, a CDK1 inhibitor, could preferentially induce cell death in ESCs while sparing differentiated cells... In the present study, the authors used an alternative CDK inhibitor, dinaciclib, developed by Merck, with improved pharmacokinetic properties compared to purvalanol A... Therefore, the authors treated mouse ESCs with flavopiridol, a CDK9 inhibitor, and observed that Nanog and c-Myc expressions were greatly decreased (Wu et al. )... Further elucidation will be needed to examine whether CDK9 inhibition is associated with ESC survival... When we utilize iPSC-derived cells for clinical application, there are two types of tumor cells; a tumor (i.e. benign teratoma) derived from undifferentiated cells, and a tumor derived from differentiated cells... Although we can prevent teratoma formation (the former part) by using emerging technology as mentioned above, it would be essential to pre-examine genome sequence of iPSC-derived products in order to prevent the occurrence of malignant tumors (the latter part)... In summary, now, we can choose or combine several ways of preventing teratoma formation, depending on efficacy and safety/toxicity, via ex vivo purging of undifferentiated cells.

No MeSH data available.


Related in: MedlinePlus

Recent advances in selective elimination of human and/or mouse pluripotent stem cells. (A) A recombinant lectin-toxin fusion protein (rBC2LCN-PE23) preferentially binds to and is internalized by human pluripotent stem cells, thus killing human pluripotent stem cells selectively (Tateno et al. 2015). (B) CDK1 inhibitors (Purvalanol A and Dinaciclib) are potent in inducing apoptosis in human and mouse ESCs. Treatment with a CDK1 inhibitor is demonstrated to prevent tetatoma formation (Huskey et al. 2015). (C) A CDK9 inhibitor (Flavopiridol) is shown to decrease Nanog and c-Myc expressions in mouse ESCs (Wu et al. 2015). It remains to be determined whether CDK9 inhibition results in prevention of teratoma formation
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4491051&req=5

Fig1: Recent advances in selective elimination of human and/or mouse pluripotent stem cells. (A) A recombinant lectin-toxin fusion protein (rBC2LCN-PE23) preferentially binds to and is internalized by human pluripotent stem cells, thus killing human pluripotent stem cells selectively (Tateno et al. 2015). (B) CDK1 inhibitors (Purvalanol A and Dinaciclib) are potent in inducing apoptosis in human and mouse ESCs. Treatment with a CDK1 inhibitor is demonstrated to prevent tetatoma formation (Huskey et al. 2015). (C) A CDK9 inhibitor (Flavopiridol) is shown to decrease Nanog and c-Myc expressions in mouse ESCs (Wu et al. 2015). It remains to be determined whether CDK9 inhibition results in prevention of teratoma formation

Mentions: Accumulating evidence demonstrates several interesting methods of depleting undifferentiated cells, as shown previously (Masuda et al., 2014). We can classify these methods as positive selection or negative selection; in positive selection, differentiated cells that are positive for differentiation markers would be collected, whereas in negative selection, undifferentiated cells would be discarded, thus enabling to eliminate tumorigenic cells from iPSC-derived products. For negative selection, in most cases, molecular-targeted drugs have been used to kill iPSCs, such as small chemicals or antibodies (especially those conjugated with cytotoxic drugs). Very recently, three papers (Tateno et al., 2015; Huskey et al., 2015; Wu et al., 2015) have been published, demonstrating that novel different methods might be useful for removing tumorigenic iPSCs (Table 1) (Fig. 1).Table 1


Eliminating residual iPS cells for safety in clinical application.

Masuda S, Miyagawa S, Fukushima S, Sougawa N, Okimoto K, Tada C, Saito A, Sawa Y - Protein Cell (2015)

Recent advances in selective elimination of human and/or mouse pluripotent stem cells. (A) A recombinant lectin-toxin fusion protein (rBC2LCN-PE23) preferentially binds to and is internalized by human pluripotent stem cells, thus killing human pluripotent stem cells selectively (Tateno et al. 2015). (B) CDK1 inhibitors (Purvalanol A and Dinaciclib) are potent in inducing apoptosis in human and mouse ESCs. Treatment with a CDK1 inhibitor is demonstrated to prevent tetatoma formation (Huskey et al. 2015). (C) A CDK9 inhibitor (Flavopiridol) is shown to decrease Nanog and c-Myc expressions in mouse ESCs (Wu et al. 2015). It remains to be determined whether CDK9 inhibition results in prevention of teratoma formation
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4491051&req=5

Fig1: Recent advances in selective elimination of human and/or mouse pluripotent stem cells. (A) A recombinant lectin-toxin fusion protein (rBC2LCN-PE23) preferentially binds to and is internalized by human pluripotent stem cells, thus killing human pluripotent stem cells selectively (Tateno et al. 2015). (B) CDK1 inhibitors (Purvalanol A and Dinaciclib) are potent in inducing apoptosis in human and mouse ESCs. Treatment with a CDK1 inhibitor is demonstrated to prevent tetatoma formation (Huskey et al. 2015). (C) A CDK9 inhibitor (Flavopiridol) is shown to decrease Nanog and c-Myc expressions in mouse ESCs (Wu et al. 2015). It remains to be determined whether CDK9 inhibition results in prevention of teratoma formation
Mentions: Accumulating evidence demonstrates several interesting methods of depleting undifferentiated cells, as shown previously (Masuda et al., 2014). We can classify these methods as positive selection or negative selection; in positive selection, differentiated cells that are positive for differentiation markers would be collected, whereas in negative selection, undifferentiated cells would be discarded, thus enabling to eliminate tumorigenic cells from iPSC-derived products. For negative selection, in most cases, molecular-targeted drugs have been used to kill iPSCs, such as small chemicals or antibodies (especially those conjugated with cytotoxic drugs). Very recently, three papers (Tateno et al., 2015; Huskey et al., 2015; Wu et al., 2015) have been published, demonstrating that novel different methods might be useful for removing tumorigenic iPSCs (Table 1) (Fig. 1).Table 1

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

First-in-human clinical trial for age-related macular degeneration using iPSC-derived retinal pigment epithelium (RPE) cells was conducted in 2014, showing no serious adverse effects to date, including tumor formation... However, in the case of clinical trial using iPSC-derived cardiomyocytes, 10–10 cells would be required for transplantation; strict control of residual undifferentiated cells should be necessary for safer clinical application... Previously, Tateno and colleagues discovered that a lectin, called rBC2LCN, binds to human iPSCs and embryonic stem cells (ESCs), but not to differentiated cells (Tateno et al. )... Notably, lectin-toxin fusion protein (rBC2LCN-PE23) could bind to and successfully be internalized by human iPSCs, suggesting that lectin (rBC2LCN) could be useful for delivery of cytotoxic agents into human iPSCs... Furthermore, within 24 h, complete elimination of human iPSCs was achieved by culture in the presence of lectin-toxin fusion protein, indicating that rBC2LCN-PE23 exerts a robust cytotoxic effect on human iPSCs... On the other hand, it has a negligible cytotoxic effect on differentiated cells, thereby enabling selective elimination of human iPSCs in a mixed cell population (Tateno et al. )... In the present study by Tateno and colleagues, although selective elimination of human iPSCs was examined in a mixed cell population (where human fibroblasts were spiked by human iPSCs) (Tateno et al. ), differentiated cells (derived from human iPSCs) containing undifferentiated cells should be examined precisely in the future... The authors demonstrated that purvalanol A, a CDK1 inhibitor, could preferentially induce cell death in ESCs while sparing differentiated cells... In the present study, the authors used an alternative CDK inhibitor, dinaciclib, developed by Merck, with improved pharmacokinetic properties compared to purvalanol A... Therefore, the authors treated mouse ESCs with flavopiridol, a CDK9 inhibitor, and observed that Nanog and c-Myc expressions were greatly decreased (Wu et al. )... Further elucidation will be needed to examine whether CDK9 inhibition is associated with ESC survival... When we utilize iPSC-derived cells for clinical application, there are two types of tumor cells; a tumor (i.e. benign teratoma) derived from undifferentiated cells, and a tumor derived from differentiated cells... Although we can prevent teratoma formation (the former part) by using emerging technology as mentioned above, it would be essential to pre-examine genome sequence of iPSC-derived products in order to prevent the occurrence of malignant tumors (the latter part)... In summary, now, we can choose or combine several ways of preventing teratoma formation, depending on efficacy and safety/toxicity, via ex vivo purging of undifferentiated cells.

No MeSH data available.


Related in: MedlinePlus