Acquired genetic changes in human pluripotent stem cells: origins and consequences

Area of Science:

• Stem cell biology
• Genetics
• Regenerative medicine

Background:

• Human pluripotent stem cells (hPSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), are vital for regenerative medicine.
• Long-term culture of hPSCs can lead to the accumulation of genetic alterations, such as chromosomal abnormalities and mutations in cancer-associated genes (e.g., TP53).
• These acquired genetic changes pose significant safety risks for hPSC-derived cell therapies.

Purpose of the Study:

• To review the types of genetic mutations acquired by human pluripotent stem cells (PSCs).
• To discuss the mechanisms underlying the accumulation of these mutations.
• To address the safety implications of PSC genetic instability for regenerative medicine.

Main Methods:

• Review of existing literature on genetic alterations in human pluripotent stem cells (PSCs).
• Analysis of mutation types, including chromosomal gains/losses and gene mutations (e.g., TP53).
• Discussion of mechanisms driving mutation acquisition and selection in PSCs.

Main Results:

• Human PSCs commonly acquire genetic changes like chromosomal aberrations and mutations in cancer-associated genes during prolonged culture.
• Despite a low underlying mutation rate, PSCs exhibit susceptibility to genomic damage.
• PSC genetic variants often confer a selective growth advantage, leading to their prevalence despite being rare events.

Conclusions:

• Genetic instability in PSCs is a critical concern for the clinical application of cell therapies.
• Understanding the mechanisms of PSC mutation accumulation is essential for developing safer cell-based regenerative treatments.
• Current detection methods may fail to identify low-frequency mutations, necessitating improved monitoring strategies.