Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells - PubMed (original) (raw)

Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells

Zhumur Ghosh et al. Cancer Res. 2011.

Abstract

Pluripotent stem cells, both human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC), can give rise to multiple cell types and hence have tremendous potential for regenerative therapies. However, the tumorigenic potential of these cells remains a great concern, as reflected in the formation of teratomas by transplanted pluripotent cells. In clinical practice, most pluripotent cells will be differentiated into useful therapeutic cell types such as neuronal, cardiac, or endothelial cells prior to human transplantation, drastically reducing their tumorigenic potential. Our work investigated the extent to which these differentiated stem cell derivatives are truly devoid of oncogenic potential. In this study, we analyzed the gene expression patterns from three sets of hiPSC- and hESC-derivatives and the corresponding primary cells, and compared their transcriptomes with those of five different types of cancer. Our analysis revealed a significant gene expression overlap of the hiPSC- and hESC-derivatives with cancer, whereas the corresponding primary cells showed minimum overlap. Real-time quantitative PCR analysis of a set of cancer-related genes (selected on the basis of rigorous functional and pathway analyses) confirmed our results. Overall, our findings suggested that pluripotent stem cell derivatives may still bear oncogenic properties even after differentiation, and additional stringent functional assays to purify these cells should be done before they can be used for regenerative therapy.

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Figures

Figure 1

Global gene expression pattern showing gene expression overlap (in percentage) of the following groups: (A) cancer versus hiPSC-HEP, hESC-HEP, and HEP; (B) cancer versus hiPSC-EC, hESC-EC, HUVEC; and (C) cancer versus hiPSC-NCC, hESC-NCC, and NCC. Gene expression overlap is highest between cancer cell lines and hiPSC-derivatives compared to primary cells.

Figure 2

Cancer specific gene expression analysis for cancer, hESC- and hiPSC-derived hepatocytes, and primary hepatocytes. (A) Matrix showing the distance measures among the four cell types. (B) Hierarchical cluster analysis of the four cell types.

Figure 3

Cancer specific gene expression analysis for cancer, hESC- and hiPSC-derived endothelial cells, and HUVEC. (A) Matrix showing the distance measures among the four cell types. (B) Hierarchical cluster analysis of the four cell types.

Figure 4

Cancer specific gene expression analysis for cancer, hESC- and hiPSC-derived neural crest cells, and neural crest cells. (A) Matrix showing the distance measures among the four cell types. (B) Hierarchical cluster analysis of the four cell types.

Figure 5

Relative distance measures between (A) cancer cells versus hESC- and hiPSC-derived hepatocytes and primary hepatocyte cells; (B) cancer cells versus hESC- and hiPSC-derived endothelial cells and HUVEC; and (C) cancer cells versus hESC- and hiPSC-derived neural crest cells and neural crest cells.

Figure 6

Venn diagram showing the common cancer genes from the three data sets. Note there are 20 cancer genes that are common among the three data sets.

Figure 7

(A) qRT-PCR data analysis and validation of 10 selected common cancer genes in hiPSC-EC and hESC-EC relative to HUVEC at passage < 5. (B) Western blot analysis of TNC, SEMA5A, PCOLCE, and COL6A2 in hiPSC-EC and hESC-EC as compared to HUVEC confirms increased expression at protein level. (C) qRT-PCR data of the selected common cancer genes in four cancer cell lines (treated with EC-medium, as well as untreated), hiPSC-EC, and hESC-EC relative to HUVEC. There was no significant change in the gene expression pattern of the cancer cell lines on treatment with EC-medium. (D) qRT-PCR data of the selected common cancer genes in nonviral minicircle reprogrammed hiPSC-derived EC (mc-hiPSC-EC), lentiviral reprogrammed hiPSC-derived EC (hiPSC-EC), and hESC-EC relative to HUVEC.

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Dissecting the oncogenic and tumorigenic potential of differentiated human induced pluripotent stem cells and human embryonic stem cells - PubMed (original) (raw)