Senior Researcher Korea National Institute of Health, Republic of Korea
Abstract: Human pluripotent stem cells (hPSCs) possess the unique ability to proliferate indefinitely and differentiate into various cell types in the human body, making them a promising source for cell-based therapies. However, to ensure their safety as a therapeutic source, it is essential to perform tumorigenicity tests on the differentiated cells derived from hPSCs. In this study, neural progenitor cells derived from seven CMC-hiPSC lines and one H1 hESC line were injected into NOG mice, a severely immunodeficient mouse model, and monitored for 10 months. Remarkably, 6 out of the 8 hPSC lines developed abnormal phenotypes, including brain tumors and choroid plexus tumors, raising concerns about the safety of these cells for therapeutic use. To further investigate the underlying genetic changes, we analyzed gene expression patterns in the neural progenitor cells using transcriptomic data. RNA sequencing (RNA-seq) revealed a significant increase in the expression of genes associated with nervous system development, particularly CNTN2 and CHL1, in the tumor-forming groups compared to the non-tumor groups. Additionally, Gene Set Enrichment Analysis (GSEA) of the RNA-seq data identified a suppression of PD-L1 expression and the PD-1 checkpoint pathway in the tumor-forming groups, both of which are key mechanisms of immune evasion in cancer. The accumulation of mutations during the long-term culture of hPSCs poses significant risks to the safety and efficacy of cell-based therapies. In this context, transcriptomic analysis not only provides gene expression patterns but also helps identify genetic mutations that may compromise the safety of hPSC-based therapies. Accumulating safety data, including information on genetic mutations and gene expression, is crucial for optimizing the clinical application of cell therapies. This will ultimately ensure the safety and efficacy of hPSCs as therapeutic cells, facilitating their safe implementation in clinical settings.
