Heart Cells Injected with Gene Become Biologic Pacemakers

Scientists have engineered ordinary heart cells to become exact duplicates of highly specialized pacemaker cells by injecting a single gene called Tbx18—a significant move forward in the long search for a biologic therapy to cure damaged and failing heartbeats.

The new development was described online in the journal Nature Biotechnology December 16, 2012. “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,” said Hee Cheol Cho, PhD, a Cedars-Sinai Heart Institute (Los Angeles, CA, USA) research scientist.

Pacemaker cells generate electrical activity that spreads to other heart cells in an orderly pattern to create rhythmic muscle contractions. If these cells go awry, the heart pumps erratically at best; patients healthy enough to undergo surgery often look to an electronic pacemaker as the only option for survival.

The heartbeat originates in the sinoatrial node (SAN) of the heart’s right upper chamber, where pacemaker cells are gathered. Of the heart’s 10 billion cells, less than 10,000 are pacemaker cells, also called SAN cells. Once reprogrammed by the Tbx18 gene, the newly generated pacemaker cells—induced SAN cells (iSAN cells)—had all similar characteristics of native pacemakers and maintained their SAN-like characteristics even after the effects of the Tbx18 gene had weakened.

However, the Cedars-Sinai researchers, employing a virus engineered to carry a single gene (Tbx18) that plays a key role in embryonic pacemaker cell development, directly reprogrammed cardiomyocytes to specialized pacemaker cells. The new cells took on the distinctive features and function of native pacemaker cells, both in lab cell reprogramming and in guinea pig studies.

Earlier attempts to generate new pacemaker cells resulted in heart muscle cells that could beat on their own. Nevertheless, the engineered cells were closer to typical muscle cells than to pacemaker cells. Other applications employed embryonic stem cells to generate pacemaker cells. However, the risk of contaminating cancerous cells is a persistent hurdle to realizing a therapeutic potential with the embryonic stem cell-based approach. The new work, with astonishing simplicity, creates pacemaker cells that closely resemble the native ones free from the risk of cancer.

For his contributions to biologic pacemaker technology, Dr. Cho recently won the Louis N. and Arnold M. Katz Basic Research Prize, a prestigious young investigator award of the American Heart Association. “This is the culmination of 10 years of work in our laboratory to build a biological pacemaker as an alternative to electronic pacing devices,” said Eduardo Marbán, MD, PhD, director of the Cedars-Sinai Heart Institute and an innovator involved in cardiac stem cell research. A clinical trial of Dr. Marbán’s stem cell therapy for myocardial infarct patients recently found the investigational treatment helped damaged hearts regrow healthy muscle.

If additional studies validate and support findings of the pacemaker cell studies, the researchers reported that they believe therapy might be administered by injecting Tbx18 into a patient’s heart or by creating pacemaker cells in the laboratory and transplanting them into the heart. But additional studies of safety and effectiveness must be conducted before human clinical trials could begin.

Related Links:
Cedars-Sinai Heart Institute