Induced Stem Cells Require Caution

Several studies have found that the stem cell “reprogramming” processes can lead to dangerous abnormalities.
Article Highlights:
  • Induced pluripotent stem cells (iPSCs) have been proposed as therapeutic agents to treat degenerative diseases and as a way to study such diseases "in a dish."
  • IPSCs can elicit an unwanted immune response in transplant recipients and develop potentially dangerous genetic and chromosomal abnormalities.
  • Experts urge caution in the use of iPSCs as treatments and in drawing conclusions from "disease in a dish" models.
by Margaret Wahl on January 1, 2012 - 1:42pm

QUEST Vol. 19, No. 1

Stem cells have been much in the news lately, including for neuromuscular diseases.

One extremely promising approach has been to create stem cells from the adult (differentiated) cells of humans or animals, and then reprogram them back to a stemlike state, after which they can be redifferentiated into a desired cell type, such as muscle or nerve cells. Stem cells made from differentiated cells are called induced pluripotent stem cells, or iPSCs.

One research group, which published its results in March 2011 in the journal Stem Cells, found that immature muscle cells called myoblasts can be reprogrammed into muscle stem cells that might be useful for studying muscle disease or even treating it.

And an MDA-supported team reported June 17, 2011, in Human Molecular Genetics, that it had created a “disease in a dish” model of one form of amyotrophic lateral sclerosis (ALS) by reprogramming skin cells taken from patients into ALS-affected stem cells.

Although it’s hoped that iPSCs can be used in both research and transplantation strategies, several concerns have been raised about the safety and utility of these cells — such as whether iPSCs can elicit an immune response when transplanted — and modifications in laboratory procedures may need to take place.

That immune responses and other serious problems that can arise with induced pluripotent stem cells doesn’t mean these important cells should be abandoned. However, several issues must be addressed before such cells can be considered safe to transplant into people and before “disease in a dish” models based on iPSCs can be considered reliable research models of a disease.

Reprogramming caused cancer-like mutations

Investigators in Switzerland and Italy found that when they reprogrammed mouse skin and mammary cells into iPSCs using three different methods, all three approaches resulted in genetic abnormalities.

Worse yet, the mutations resembled those found in cancer cells, leading investigators to urge refinement of the reprogramming process. The findings were reported Feb. 11, 2011, in the journal Cell Death & Differentiation.

Changes seen in genes, chromosomes

Christine Mummery at Leiden University Medical Center in the Netherlands voiced similar concerns June 2, 2011, in the New England Journal of Medicine, citing experiments in which human iPSCs made from skin cells developed genetic and chromosomal changes.

These included duplications in parts of chromosomes 12 and 20; failure of some genes to fully reprogram back to a stem cell state; and mutations that could affect genes essential for cell growth, tumor suppression or other critical functions. Mummery notes that it probably would be unwise to use iPSCs in patients until more is known about these abnormalities.

Mummery also raised questions about using iPSCs as “disease in a dish” models for examining disease processes and testing new treatments. She said that investigators can’t at this stage be certain whether the phenomena they’re observing are caused by the original mutation in the patient’s cells or by “some other mutation introduced during reprogramming.”

Additional concerns were expressed Aug. 19, 2011, in the journal Stem Cells, when scientists at the Max Planck Institute for Molecular Genetics in Berlin and other institutions discovered that human iPSCs harbored mutations in genes in their mitochondria, the cellular energy production centers that have their own DNA.

Shift in priorities advised

Bonnie Barrilleaux and Paul Knoepfler at the University of California, Davis and Shriners Hospital for Children in Sacramento, Calif., recently called for a “shift in priorities” in studies involving human iPSCs. These authors published an editorial Aug. 5, 2011, in Cell Stem Cell.

They say the focus should be on the “issues most relevant to eventual clinical use of the cells,” such as understanding the potential of these cells to elicit an immune response; making sure the reprogramming process does not introduce possibly harmful genetic or other changes; and checking carefully to make sure iPSCs don’t form tumors.

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