Skin Cells Reprogrammed Into Beating Heart Tissue

Imagine a future when your aging organs - a failing liver, or a brain degenerated by Alzheimer's disease - could be repaired using cells from other parts of your body.  That dream came closer to reality recently when Wisconsin researchers announced that skin cells have been genetically reprogrammed into beating cardiac (i.e. heart) tissue.

In a UW-Madison news release, co-author Tim Kamp put the research into context.  “If you have a heart failure patient who is in dire straits - and there are never enough donor hearts for transplantation - we may be able to make heart cells from the patient's skin cells and use them to repair heart muscle. That's pretty exciting.”  The study was published this month in the journal Circulation Research.

MSNBC did a short segment on this story, as seen below:

The goal of the research was to compare iPS cells (derived from skin) with embryonic stem cells in their ability to differentiate into cardiac tissue. Amazingly, the skin cells in the study were able to be reprogrammed into a variety of different types of cardiomyocytes (i.e. heart cells), including nodal, atrial, and ventricular tissue types.  iPS cell samples showed normal patterns of cardiac gene expression, cell proliferation, and organization of muscle sarcomeres.  As seen in a video released (at the bottom of this post) by the researchers, the tissue is capable of carrying the action potentials which propagate across a beating heart.  The tissue even pumps more quickly in response to beta-adrenergic stimulation, a component of fight-or-flight physiology.

"It's a very mysterious and complicated dance to get these cells to go from skin cells to stem cells to heart cells," says Kamp.

So how exactly did they reprogram skin cells into functional heart tissue?  It all starts with induced pluripotency,  a technique pioneered in 2007 by which adult somatic cells are dedifferentiated (unspecialized) back into stem cells by tweaking their gene expression.  First, human skin cells are isolated and cultured to act as hosts.  Next, certain genes that normally maintain pluripotency in embryonic stem cells - such as Oct4, Sox2, and NANOG - are transfected into the host cells using viral vectors that attach themselves into the cell's genome.  After a few weeks in culture, a small number of transfected cells begin to take on characteristics of embryonic stem cells: they become induced pluripotent stem cells.  These iPS cells are then differentiated using the embryoid body (EB) method, in which stem cells are induced to recapitulate the process of embryonic development.  The EB method produces cardiac tissue as part of the embryoid body.  After the cells have differentiated, the pluripotency genes are downregulated - put into a negative feedback loop - that allows the cells to maintain their assumed form.  To summarize: skin cells are reprogrammed into undifferentiated pluripotent cells, and then redifferentiated to produce the desired cell type: cardiac tissue.

Organ transplantation is a notoriously difficult procedure in modern medicine.  If transplanted tissue isn't a perfect match for the recipient's body, the immune system will reject the organ and attack it as a foreign invader (as it would attack bacteria).  Finding an appropriate donor takes a careful consideration of blood type and antibody response, restrictions that limit the options for potential recipients.   iPS cell transplants avoid these difficulties.  Because the tissue comes from a patient's own skin, the transplant is autologous and the risk of immune rejection is minimized.

While the production of cardiac cells from iPSCs is certainly an exciting breakthrough, it is only one example of a wide range of research being done in pluripotency.  Because the process of differentiation follows the process of embryonic development, iPS cells can be reprogrammed into a number of desirable products.  In addition to cardiac cells, iPS cells have been successfully differentiated into neurons.   As our ability to change one cell type into another increases, new breakthroughs will allow unprecedented advances in the medical field.

Research into iPS cells sidesteps the ethical and political controversies surrounding embryonic stem cells, and many researchers hope that they may hold the same promise in clinical application.  Still, the techniques aren’t ready for therapy.  The use of a virus to insert transcription factors into the cellular genetic code carries with it a risk of forming a tumor.  While the tissue derived by these methods isn’t ready for transplantation, the results are an important milestone for research and may soon be safe enough for clinical use.

You can see the beating heart tissue from the Wisconsin study below: