Induced Stem Cells Require Cautious Approach

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.

In January 2011, researchers showed 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 in June, an MDA-supported team announced the creation of a "disease in a dish" model of one form of amyotrophic lateral sclerosis (ALS), made 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 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 patients and before "disease in a dish" models based on iPSCs can be considered reliable mimics of a disease.

Here’s a summary of some of the challenges facing stem-cell research going forward, with links to more information.

Reprogramming caused cancer-like mutations in mouse cells

In February 2011, when investigators in Switzerland and Italy reprogrammed mouse skin and mammary cells into iPSCs using three different methods, they found all three approaches resulted in genetic abnormalities. Worse yet, the mutations the scientists saw in the iPSCs resembled those found in cancer cells, causing them to urge refinement of the reprogramming process.

For more, see:

Potentially dangerous changes in genes, chromosomes seen in reprogrammed human cells

Christine Mummery of Leiden University Medical Center in the Netherlands voiced similar concerns in June 2011, citing experiments in which human iPSCs made from skin cells developed genetic and chromosomal changes, including: 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."

See Induced Pluripotent Stem Cells — A Cautionary Note for a link to the first 100 words of this editorial in the June 2, 2011, issue of the New England Journal of Medicine and a way to purchase the full article.

Mitochondria of human iPSCs can contain mutations

Additional concerns were expressed in August 2011, 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.

For more, see:

Experts advise caution, shift in priorities

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.

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.

See Perspective: Inducing iPSCs to Escape the Dish, to read a summary of Barrilleaux's and Knoepfler's editorial, published Aug. 5, 2011, in Cell Stem Cell.

Disease: 
Link: 
GUID: 
19 531
Time Stamp: 
1 322 062 121
Thumbnail: 
http://quest.mda.org/sites/default/files/imagecache/mda_org_frontpage100x75/StemcellLeadArt.jpg
Node Type: 
Quest News