Clinicians use stem cell treatments in clinical trials for eye disease, spinal cord injury, and type 1 diabetes. Their goal is to transplant stem cells or their derivatives to replace damaged tissue, restore function, and cure patients. This aim is to do this while keeping treatments safe and free of harmful side effects.
Safety is essential for stem cell therapies. As such, early gene‑therapy trials showed this clearly, when genetically altered stem cells meant to help patients instead caused cancer. Although newer gene‑therapy methods appear safe, concerns remain about generating pluripotent stem cells. These cells will play a major role in future cell‑replacement therapies.
Stem cell reprogramming can cause problems
Induced pluripotent stem cells, or iPS cells, are a promising source of pluripotent cells for therapy. They match embryonic stem cells but can be created from adult tissues like skin or blood. Reprogramming turns some genes off and others on through epigenetic remodeling, which alters chromatin and controls gene expression.
To produce healthy iPS cells, the reprogramming steps and epigenetic changes must align precisely. Scientists worry these steps can fail and introduce cancer‑causing mutations that might form tumors after transplantation.
A CIRM-funded study published Friday in Nature Communications offers some relief to this potential roadblock to using reprogrammed iPS cells for cell therapy. Scientists from The Scripps Research Institute (TSRI) and the J. Craig Venter Institute (JCVI) collaborated on a study that assessed the safety of three common methods for generating iPS cells. Their findings suggest that these reprogramming methods are relatively safe and unlikely to give cancer-causing mutations to patients.
Comparing three reprogramming methods
Scientists typically create iPS cells by activating four genes — OCT4, SOX2, KLF4, and c‑MYC. This is in order to keep cells pluripotent. The approach forces adult cells to express these genes by adding extra copies. In this study, the team compared three common reprogramming methods. This is done by integrating retroviral vectors, non‑integrating Sendai virus, and synthetic mRNAs. This allows scientists to look for cancer‑causing mutations in iPSC DNA.
Unlike earlier studies that examined one mutation type, the researchers looked for many. The researchers searched for changes ranging from single‑base shifts to large structural variants. They compared whole‑genome sequencing from the original skin cells to the resulting iPS cells.
The three methods did not cause serious mutations. The team suggested that cancer‑linked changes likely occur later, during iPS cell expansion in culture, a problem they are now studying.
“We detected subtle differences in the number of variants depending on the method,” the researchers explained. “We rarely found mutations in genes associated with increased cancer risk.”
Mutations reported in iPS cell cultures are unlikely to come from reprogramming, according to the researchers. Instead they come from the selective pressures that occur when human pluripotent stem cells are expanded in culture.
The safety of patients comes first
To ensure iPSC reprogramming methods were safe for patients, Jeanne Loring examined whether the cells were prone to mutations.
“We wanted to know whether reprogramming cells would make them prone to mutations,” Loring said. “The answer is no. The methods we use to make pluripotent stem cells are safe.”
“The safety of patients comes first, and hopefully will spark further interest,” said Nicholas Schork.
Moving from bench to clinic
Clinicians use stem cell treatments in clinical trials for eye disease, spinal cord injury, and type 1 diabetes. They aim to transplant stem cells or their derivatives to replace damaged tissue, restore function, and cure patients—while keeping treatments safe and free of harmful side effects.
Safety is essential for stem cell therapies. Early gene‑therapy trials proved this when genetically altered stem cells, intended to help patients, instead caused cancer. Newer gene‑therapy methods appear safe, but concerns remain about generating pluripotent stem cells. These cells will play a major role in future cell‑replacement therapies.
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Using reprogramming methods with stem cells can become a guarantee to save millions of people! Sounds optimistic!