In a paper published online before print in Nature Biotechnology on 16 December, the researchers, from the Cedars-Sinai Heart Institute in Los Angeles, California, describe how they used a virus to inject a single gene (Tbx18) into heart muscle cells to reprogram them to become exact replicas of highly specialized pacemaker cells .
Senior author Hee Cheol Cho, a research scientist at the Heart Institute, says in a statement:
"Although we and others have created primitive biological pacemakers before, this study is the first to show that a single gene can direct the conversion of heart muscle cells to genuine pacemaker cells."
"The new cells generated electrical impulses spontaneously and were indistinguishable from native pacemaker cells," he adds.
Pacemaker CellsThe heart is a finely tuned instrument that pumps blood around the body in a regulated beat or rhythm. Pacemaker or sinoatrial node (SAN) cells are specialized cells that generate and send highly ordered electrical pulses to heart muscle cells to make them contract rhythmically.
The electrical signal they produce is known as a sinus rhythm and can be recorded with an electrocardiogram (ECG).
The heart contains 10 billion cells, but fewer than 10,000 of these are pacemaker cells.
A correct and healthy sinus rhythm ensures that the two upper and two lower chambers of the heart contract at precisely the right time to ensure blood is pumped smoothly, sending oxygen-rich blood to the body and bringing oxygen-starved blood back again to be replenished in the lungs.
The sinus rhythm starts in the sinoatrial node (SAN) of the heart's right upper chamber, where pacemaker cells are clustered.
When pacemaker cells malfunction, the heart pumps erratically and often the only option for survival is to have an electronic pacemaker fitted, but this can realistically only be done for patients healthy enough to undergo surgery.
From Heart Cell to Pacemaker Cell Using Single GeneThe Cedars-Sinai researchers used a virus engineered to insert a single gene, the Tbx18 gene, into cardiomyocytes (heart muscle cells) to convert them into pacemaker cells.
Tbx18 plays an important part in the development of pacemaker cells in the embryo.
One reprogrammed, the newly created pacemaker cells, called "induced SAN cells" or iSAN cells had all the hallmarks of native pacemakers and maintained their SAN-like features even after the effects of the Tbx18 gene had worn off.
The team tested the features both in cell cultures (in vitro), and in live guinea pigs (in vivo).
Why this Study is DifferentPrevious studies have succeeded in making pacemaker cells from heart muscle cells, and have produced pacemaker cells that can beat on their own. But the modified cells were closer to heart muscle cells than native pacemaker cells.
Others have tried using embryonic stem cells to make pacemaker cells. But this approach carries the risk of generating cancerous cells: a persistent hazard of using embryonic stem cells.
Cho and colleagues appear to have avoided these obstacles with astonishing simplicity: by inserting a single gene directly into heart muscle cells they have produced pacemaker cells that closely resemble native ones and are free from the risk of cancer.
10 Years of Work - Not Finished YetThe study is the "culmination of 10 years of work in our laboratory to build a biological pacemaker as an alternative to electronic pacing devices," says co-author Eduardo Marbán, director of the Cedars-Sinai Heart Institute and Mark S. Siegel Family Professor.
Marbán is also a pioneer in cardiac stem cell research and earlier in 2012, he and his team released results of a clinical trial where they repaired heart attack damage using patients' own stem cells to regrow healthy heart muscle.
The researchers suggest if further studies confirm their approach, then a therapy could be developed whereby Tbx18 is injected dirently into a patient's heart or by making pacemaker cells in the lab and then transplanting them into the patient's heart.
However, therapy based on this method is still a long way off, since further studies to prove safety and efficacy would also be required before human clinical trials could be considered.
Recently, the American Heart Association awarded its prestigious young investigator award, the Louis N. and Arnold M. Katz Basic Research Prize, to Cho for his work on biological pacemaker technology.
Funds from the Cedars-Sinai Board of Governors Heart Stem Cell Center, the Heart Rhythm Society, the Heart and Stroke Foundation of Canada, the American Heart Association, the National Heart, Lung, and Blood Institute and the Mark S. Siegel Family Professorship, helped finance the study.
Written by Catharine Paddock PhD