Sequencing-Based Screening Needed for Therapeutic Stem Cells

One of the potential therapeutic advantages of stem cells is that they can regenerate. But, a new study, published May 11 in Nature, suggests that the longer stem cell lines replicate the more cancer-related mutations they acquire, leading the authors to recommend that stem cells and therapies derived from them undergo “careful” genetic characterization before clinical use.

The study found that approximately 5 percent of stem cell lines analyzed developed mutations in p53, a tumor-suppressing gene, responsible for controlling cell growth and division. The authors say that stem-cell based therapies should still be investigated, but that genetic sequencing technologies should be used to screen for mutated cells in stem cell cultures. Without such screening, stem cell transplants could contain an elevated cancer risk.

“Our analyses indicate that researchers have unknowingly and routinely used [stem] cells that harbor cancer-related missense mutations in TP53,” write the authors led by Florian Merkle, Ph.D., from Harvard University. “These findings have practical implications for the use of human embryonic stem cells in disease modeling and transplantation medicine.”

The researchers sequenced the exomes of 140 independent human embryonic stem cell lines listed on the National Institutes of Health registry, which included 26 lines developed for potential clinical use.

Sequencing revealed that five unrelated cell lines carried six mutations in the TP53 gene. The TP53 mutations were the dominant negative mutations commonly seen in human cancers. The researchers also found that the fraction of TP53 mutant alleles increased with passage number under standard culture conditions, suggesting, the authors say, that the mutation may offer a growth advantage to stem cells in culture.

“Our findings indicate that an additional series of quality control checks should be implemented during the production of stem cells and their downstream use in developing therapies,” said coauthor Kevin Eggan, Ph.D., from Harvard University. “Fortunately, these genetic checks can be readily performed with precise, sensitive, and increasingly inexpensive sequencing methods.”

Takeaway: Stem cells acquire potentially harmful p53 mutations, which should be screened for before transplantation or use for other therapeutic purposes.