Highlights:

• Stem cells isolated from brown fat tissue differentiated into two kinds of beating cells in lab dishes.
• The beating cells had characteristics of the heart’s pacemaker cells and conduction system cells.
• Implantation of the beating cells partially or fully reversed chemically induced heart block in half of test mice after one week, while control mice showed no change.

DALLAS, July 22, 2009 — Stem cells isolated from brown fat tissue grew into beating cells in lab dishes and partially or fully reversed an electrical problem in the hearts of half of the mice in which they were implanted, according to a new study. Japanese researchers reported the findings at the American Heart Association’s Basic Cardiovascular Sciences Conference 2009 – Molecular Mechanisms of Cardiovascular Disease.

“Electronic pacemakers are often used as palliative therapy (helpful but not curative treatment) for people who have conduction problems with the electrical signals that govern the heartbeat. However, that therapy has several shortcomings, including possible malfunction and the need for repeated replacement of the devices’ power packs and electrodes,” said Toshinao Takahashi, M.D., lead author and research fellow at Chiba University Graduate School of Medicine in Chiba, Japan. “Cell therapy could overcome those problems and provide a possible cure for conductive disease. Our goal is to create a biological pacemaker.”

The human body has two kinds of fat tissue: brown fat and white fat. Brown fat tissue is one source of mesenchymal stem cells. Earlier studies showed that these cells had the ability to differentiate into many kinds of cells such as bone, neuron, muscle, liver and fat cells, Takahashi explained.

The researchers isolated mesenchymal stem cells from mouse brown fat tissue and grew them in a lab dish, nourishing them with nutrients like blood serum. After four to seven days, the researchers noticed two distinct kinds of cells that showed spontaneous beating. The first were single round cells that beat individually. The second kind were groups of multiple cells that had arranged themselves into tube-like structures and were beating as independent groups, he said.

“Some of the tube-like groups of cells looked like the fine muscle fibers seen in heart muscle,” Takahashi said.

Chemical analysis revealed that most of the round and tube-like cells in beating colonies created two proteins specific to heart muscle — sarcomeric alpha actinin and cardiac Troponin T — as well as other chemical markers characteristic of the heart’s conductive tissue, he said.

In addition, the spontaneous electrical activity seemed to be in the same range as the heart’s pacemaker activity, with an electrical potential (mV) between -40 to -60 mV. Plus, the two types of beating cells showed properties of both the heart’s pacemaker cells, which govern heartbeat, and the nerve cells that carry, or conduct, signals along the heart’s electrical pathways, researchers said.
To study the cells’ regenerative potential in a living heart, the researchers reduced heart rate in eight test mice and four control mice by chemically blocking electrical signals through a process called atrioventricular (AV) block. The scientists injected beating cells that had been tagged to glow green into the test mice and injected white fat tissue into the control mice.

One week after transplantation, half of the test mice had fully or partially overcome their AV block. (Two had complete AV block reversal and two had 50 percent reversal.) In comparison, none of the control mice showed any change, he said.

Later analysis revealed green-tagged cells in the area of the heart that plays a central role in the heart’s electrical conduction systems.

“Our findings suggest that brown-fat-derived mesenchymal stem cells differentiate into cardiac conduction system and pacemaker-like cells in vitro (in a lab dish) and in vivo (in a living organism) and may become a useful cell source for antiarrhythmic therapy,” Takahashi said.

Co-authors are: Toshio Nagai, M.D., Ph.D.; Masato Kanda, M.D.; Masakuni Tokunaga, Ph.D.; Meiran Liu, M.D.; Atsuhiko T. Naito, M.D., Ph.D.; Takehiko Ogura, M.D., Ph.D.; Jong-Kook Lee, M.D., Ph.D.; Itsuo Kodama, M.D., Ph.D.; and Issei Komuro, M.D., Ph.D. Individual author disclosures can be found on the abstract.

This study was supported by a Grant-in-Aid for Scientific Research, Developmental Scientific Research, and Scientific Research on Priority Areas from the Ministry of Education, Science, Sports, and Culture, and Health and Labour Sciences Research Grants.

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NR09-1087 (BCVS/Takahashi)