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Summary of disseration

Human pluripotent stem cells (hPSCs), including embryonic and induced pluripotent stem cells, have transformed biomedical research thanks to their ability to self-renew and differentiate into any cell type off the human body. They hold enormous potential for disease modeling, regenerative medicine, and tissue engineering. However, a major safety concern is their potential to form malignant tumors, as some hPSC lines develop rapidly dividing, immature tissues when transplanted. Detecting this malignant potential reliably—ideally without animal testing—is a key challenge. This thesis investigates the issue from two angles: 1) understanding the underlying mechanisms driving malignancy and 2) exploring current and new methods for its detection.

Firstly, we observed that long-term culture often causes hPSCs to accumulate genetic abnormalities, particularly gains in certain chromosomes (notably chromosomes 20q11 and 12), which contain cancer-related genes. Mutations in TP53, a major tumor suppressor gene, are also recurrently observed in hPSCs cultured long-term. Our work reveals that these mutations induce further genetic instability and confer traits associated with cancer to the cells, even before obvious signs appear. Thus, the onset of genomic aberrations is to be avoided for preventing malignancy of hPSCs, for which routine genomic screening is proposed as the best prevention strategy.

Secondly, we explore the teratoma assay, the only accepted method to assess both stem cell pluripotency and malignancy. Despite informative, we found this assay is inconsistent, poorly standardized, and ethically problematic due to the use of animals. To address this, we developed an in vitro alternative model, using benign and malignant hPSCs, able to replicate the teratoma assay without the need of laboratory animals. While promising, further replacement of animal-derived components in the model is desired, as this would bring a universal & ethical animal-free alternative to the teratoma assay.

Overall, this work move the stem cell field towards a standardized, reproducible, and animal-free method to ensure the safe clinical use of hPSCs.

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