Stem cell progress: Turning skin cells into heart cells

Embryonic stem cell research continues to be a political and legal hot potato that stirs up a lot of emotion and argument.

In the meantime, researchers are making some remarkable progress using an alternative stem cell approach called induced pluripotent stem cells, or iPSCs (sometimes that gets  shortened to iPS).

An induced pluripotent stem cell is an adult cell, often a skin cell, that has been “reprogrammed” so it takes on the pluripotent properties of an embryonic cell. Pluripotency in this context means the capacity for a cell to generate cells of all different types. If a cell is pluripotent, it can give rise to blood cells, heart cells, kidney cells, brain cells—you name it.

Researchers at the Technical University of Munich are reporting in tomorrow’s The New England Journal of Medicine (NEJM) that they have generated working heart muscle cells—cardiomyocytes—from human skin cells using iPSCs. That’s quite a feat, but the German research team acknowledge that it has been done before (stem cell research is competitive, so firsts are important).

Their innovation was producing functional cardiomyocytes from people with an inherited condition—in this case long-QT syndrome type 1, which can lead to potentially fatal heart arrhythmias.

The heart cells their experiments produced had the genes that cause long-QT syndrome type 1. Moreover, they behaved like long-QT type 1 cardiomyocytes. When stimulated, they showed the same kind of abnormal electrical activity. They also responded to a propranolol, a beta blocker, in the same way “real” cardiomyocytes from a long-QT syndrome type 1 patient would.

Obviously you wouldn’t use these flawed cells to fix the heart of someone with the disease. But having iPSC-generated human cells that are specific to a patient and a particular condition could prove to be an ideal testing ground for research and drug development. 

Dr. Anthony Rosenzweig, a cardiovascular researcher at the Harvard Stem Cell Institute and Harvard-affiliated Beth Israel Deaconess Medical Center,  wrote an editorial about this study that was published in same issue of NEJM. This is how he put it:

Although much excitement has been generated by the potential for therapeutic delivery of such cells [iPSCs] for tissue regeneration, considerable challenges remain to make this a practical reality. A more immediate application of this technology that may also have important implications for human health lies in the development of cellular models for disease genetically matched to specific patients. Such models provide a human context for unraveling disease pathophysiology, validating therapeutic targets, and examining the response to pharmacologic interventions.

The German researchers used a retrovirus to carry four genes into the skin cells to turn them into iPSCs.  That is now the tried and true method for making iPSCs, but using retroviruses to reprogram cells raises legitimate concerns about retroviral DNA getting into the host cell’s genome and possibly having cancerous and other harmful effects.

Konrad Hochedlinger, a Harvard Stem Cell Institute researcher, has used adenoviruses, which cause the common cold, to ferry genes into cells and create iPSCs. Adenoviruses don’t insert themselves into the genome of host cells, so they would presumably be safer than retroviruses.

And just last week, another Harvard researcher, Derrick Rossi, reported that his research group had successfully reprogramned human skin cells into iPSCs using RNA, avoiding the use of viruses altogether.

Does all this progress with iPSCs mean there’s no longer a need for embyonic stem cell research? It’s a question freighted with political as well as scientific and medical significance.

“No”  is the emphatic answer from the overwhelming majority of stem cell researchers. The prevailing opinion in the field is that even if all the concerns about viral DNA and how pluripotent cells are generated were assuaged, there are still unresolved questions about whether iPSCs can ever be as pluripotent as the stem cells that come from embryos. After all, embryonic stem cells are, in a sense, naturally pluripotent and don’t have to be induced into a primordial stem state.  

There’s some reason to believe that the cells that iPSCs come from may imprint them in some way that sets limits on the cells they’re  able to generate. Perhaps iPSCs can generate some cells, not others, or there are flaws in the cells they do produce.

In an interview yesterday, Hochedlinger pointed to findings his group published in Nature earlier this year that show certain important “gene clusters” are inactive in  iPSCs but  not in embryonic stem cells (although there do seem to be ways that the iPSC gene clusters could be activated).

Here is a relevant excerpt from a profile of Francis S. Collins, director of the National Institutes of Health, in the September 6, 2010, issue of The New Yorker magazine (the Thomson-Yamanaka breakthrough is a reference to iPSCs):

When I asked Collins about the Thomson-Yamanaka breakthrough he said that not enough was yet known about such cells to guess whether they have the same therapeutic potential as embryonic stem cells. For example, scientists have learned that the pluripotent cells derived from adult tissues retain some memory of that tissue. “Will that matter for the therapeutic uses we all dream of?” he asked. “No one knows, but it would be foolish now to proceed without comparing them at every step to the gold standard for pluripotency—and that remains the human embryonic stem cell. So it’s not ‘either/or’ that we should be pursuing. It’s ‘both/and.’ ”