Improved adult-derived human stem cells have fewer genetic changes than expected

May 01, 2012

A team of researchers from Johns Hopkins University and the National Human Genome Research Institute has evaluated the whole genomic sequence of stem cells derived from human bone marrow cells—so-called induced pluripotent stem (iPS) cells—and found that relatively few genetic changes occur during stem cell conversion by an improved method. The findings, reported in the March issue of Cell Stem Cell, the official journal of the International Society for Stem Cell Research (ISSCR), will be presented at the annual ISSCR meeting in June.

“Our results show that human iPS accrue genetic changes at about the same rate as any replicating cells, which we don’t feel is a cause for concern,” says Linzhao Cheng, Ph.D., a professor of medicine and oncology, and a member of the Johns Hopkins Institute for Cell Engineering.

Each time a cell divides, it has the chance to make errors and incorporate new genetic changes in its DNA, Cheng explains. Some genetic changes can be harmless, but others can lead to changes in cell behavior that may lead to disease and, in the worst case, to cancer.

In the new study, the researchers showed that iPS cells derived from adult contain random genetic changes that do not specifically predispose the cells to form cancer.

“Little research was done previously to determine the number of DNA changes in stem cells, but because whole genome sequencing is getting faster and cheaper, we can now more easily assess the genetic stability of these cells derived by various methods and from different tissues,” Cheng says. Last year, a study published in Nature suggested higher than expected cancer gene mutation rates in iPS cells created from skin samples, which, according to Cheng, raised great concerns to many in the field pertaining to usefulness and safety of the cells. This study analyzed both viral and the improved, nonviral methods to turn on stem cell genes making the iPS cells

To more thoroughly evaluate the number of genetic changes in iPS cells created by the improved, non-viral method, Cheng’s team first converted human blood-forming cells or their support cells, so-called marrow stromal cells (MSCs) in adult bone marrow into iPS cells by turning on specific genes and giving them special nutrients. The researchers isolated DNA from--and sequenced--the genome of each type of iPS cells, in comparison with the original cells from which the iPS cells were derived.

Cheng says they then counted the number of small DNA differences in each cell line compared to the original cells. A range of 1,000 to 1,800 changes in the nucleic acid “letters” A, C, T and G occurred across each genome, but only a few changes were found in actual genes--DNA sequences that act as blueprints for our body’s proteins. Such genes make up two percent of the genome.

The blood-derived iPS cells contained six and the MSC-derived iPS cells contained 12 DNA letter changes in genes, which led the researchers to conclude that DNA changes in iPS cells are far more likely to occur in the spaces between genes, not in the genes themselves.

Next, the investigators examined the severity of the DNA changes--how likely each one would disrupt the function of each gene. They found that about half of the DNA changes were “silent,” meaning these altered blueprints wouldn’t change the nucleic acid building code for its corresponding protein or change its function.

For the remaining DNA changes, the researchers guessed these would, in fact, disrupt the function of the gene by either making the gene inactive or changing the way the gene works. Since each cell contains two copies of each gene, in many cases the other, normal copy of the gene could compensate for a disrupted gene, Cheng and the team reasoned.

Cheng cautions that disrupting a single gene copy could pose a problem though, for example, by shutting down a tumor suppressor gene that prevents cells from malignant growth. However, none of the disrupted genes his team found have been implicated in cancer.

He also noted the absence of overlap in the DNA changes found among the different stem cell lines examined, implying that the changes were random and unlikely to cluster.

Based on these findings, Cheng says, iPS cells don’t seem to pose a heightened cancer risk, but the risk is not zero, the researchers say.

“We need to sequence more iPS cell lines, including those derived from different cell types and ones using different methods of stem cell conversion, before we have a better picture of mutation rates and spectrums in the iPS cell lines,” says Paul Liu, M.D., Ph.D., co-senior author and the deputy scientific director at the National Human Genome Research Institute.

Just because these DNA changes in the don’t specifically select for cancer formation, he adds, doesn’t mean that cancer mutations can’t arise in other iPS cells. Liu adds that to be on the safe side “it should become a routine procedure to sequence iPS cells before they are used in the clinic.”

Other researchers who contributed to the study are Chunlin Zou, Bin-Kuan Chou, Sarah Dowey and Zhaohui Ye of the Johns Hopkins University; Nancy Hansen, Ling Zhao, Frank Donovan, Settara Chandrasekharappa, James Mullikin and the NISC Comparative Sequencing Program of the National Institute; and Yutao Du, Guangyu Zhou, Shijie Li and Huanming Yang of the Beijing Genomics Institute.

Explore further: Researchers successfully clone adult human stem cells

Related Stories

Correcting sickle cell disease with stem cells

Sep 28, 2011

(Medical Xpress) -- Using a patient’s own stem cells, researchers at Johns Hopkins have corrected the genetic alteration that causes sickle cell disease (SCD), a painful, disabling inherited blood disorder that affects ...

Cells derived from different stem cells: Same or different?

May 02, 2011

There are two types of stem cell considered promising sources of cells for regenerative therapies: ES and iPS cells. Recent data indicate these cells are molecularly different, raising the possibility that cells derived from ...

Stem cells reverse disease in a model of Parkinson's disease

May 16, 2011

In a new study to be published in the Journal of Clinical Investigation, researchers compared the ability of cells derived from different types of human stem cell to reverse disease in a rat model of Parkinson disease and id ...

Researchers edit genes in human stem cells

Jun 18, 2009

Researchers at the Johns Hopkins School of Medicine have successfully edited the genome of human- induced pluripotent stem cells, making possible the future development of patient-specific stem cell therapies. Reporting this ...

Stem cells, potential source of cancer-fighting T cells

Sep 20, 2011

Adult stem cells from mice converted to antigen-specific T cells -- the immune cells that fight cancer tumor cells -- show promise in cancer immunotherapy and may lead to a simpler, more efficient way to use the body's immune ...

Recommended for you

Researchers successfully clone adult human stem cells

Apr 18, 2014

( —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

Researchers develop new model of cellular movement

Apr 18, 2014

( —Cell movement plays an important role in a host of biological functions from embryonic development to repairing wounded tissue. It also enables cancer cells to break free from their sites of ...

For resetting circadian rhythms, neural cooperation is key

Apr 17, 2014

Fruit flies are pretty predictable when it comes to scheduling their days, with peaks of activity at dawn and dusk and rest times in between. Now, researchers reporting in the Cell Press journal Cell Reports on April 17th h ...

User comments : 0

More news stories

Biologists help solve fungi mysteries

( —A new genetic analysis revealing the previously unknown biodiversity and distribution of thousands of fungi in North America might also reveal a previously underappreciated contributor to climate ...

Researchers successfully clone adult human stem cells

( —An international team of researchers, led by Robert Lanza, of Advanced Cell Technology, has announced that they have performed the first successful cloning of adult human skin cells into stem ...

NASA's space station Robonaut finally getting legs

Robonaut, the first out-of-this-world humanoid, is finally getting its space legs. For three years, Robonaut has had to manage from the waist up. This new pair of legs means the experimental robot—now stuck ...

Ex-Apple chief plans mobile phone for India

Former Apple chief executive John Sculley, whose marketing skills helped bring the personal computer to desktops worldwide, says he plans to launch a mobile phone in India to exploit its still largely untapped ...

Filipino tests negative for Middle East virus

A Filipino nurse who tested positive for the Middle East virus has been found free of infection in a subsequent examination after he returned home, Philippine health officials said Saturday.

Egypt archaeologists find ancient writer's tomb

Egypt's minister of antiquities says a team of Spanish archaeologists has discovered two tombs in the southern part of the country, one of them belonging to a writer and containing a trove of artifacts including reed pens ...

Airbnb rental site raises $450 mn

Online lodging listings website Airbnb inked a $450 million funding deal with investors led by TPG, a source close to the matter said Friday.