A Massachusetts General Hospital (MGH)-led research team has identified a surprising new role for macrophages, the white blood cells primarily known for removing pathogens, cellular debris and other unwanted materials. In their paper published in Cell the investigators describe discovering that macrophages are also essential to the healthy functioning of the heart, helping conduct the electric signals that coordinate the heartbeat.
"Our finding that a new cell type is involved in cardiac conduction may lead to better understanding of normal heart function. What really surprised me was that macrophages can depolarize -- change their electric charge -- when coupled to a myocyte. Down the line, this work on the role of macrophages in conduction may lead to new treatments for cardiac arrhythmias," says corresponding author Matthias Nahrendorf, MD, PhD, of the MGH Center for Systems Biology.
Best known for their immune system activity of engulfing and digesting microbes, damaged cells and foreign substances, macrophages are found in tissues throughout the body and have recently been shown to have additional functions related to the tissues where they reside. While macrophages are required for healing damaged tissues in the heart, their presence within healthy heart muscle suggests a role in normal heart function. Nahrendorf's study was designed to investigate their potential role in transmitting and coordinating the electrical signals that stimulate heart muscle contraction.
Initial experiments in mice revealed that cardiac macrophages are more abundant in the atrioventicular (AV) node -- a key structure connecting the atria (upper chambers) to the ventricles (lower chambers) -- which coordinates contraction timing for the upper and lower chambers. Similarly high concentrations of macrophages were found in AV nodes from human autopsy samples. Subsequent animal experiments found that macrophages connect to heart muscle cells via gap junctions -- pore-like structures known to coordinate heart muscle contractions -- and that the shifts in electric charge that carry the conduction signal are synchronized between macrophages and adjacent heart muscle cells called myocytes.
Mice lacking a key gap junction protein showed an abnormal slowing of signal conduction through the AV node, and a complete depletion of tissue macrophages led to the development of AV block -- a delay in conduction between the atria and ventricles that, in human patients, requires pacemaker implantation. Overall, the findings suggest that cardiac macrophages are essential participants in the cardiac conduction system and that changes in their numbers or properties may contribute to heart rhythm abnormalities.
Nahrendorf and his colleagues are continuing to explore the role of macrophages in both the healthy heart and in common disorders of signal conduction. He adds that the cells' natural propensity to surround and take up materials for disposal could be used to induce macrophages to ingest drugs carried on nanoparticles.
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The co-lead authors of the Cell paper are Maarten Hulsmans, PhD, of the MGH Center for Systems Biology and Sebastian Clauss, MD, and Ling Xiao, PhD, of the MGH Cardiovascular Research Center. Additional co-authors include David Milan, MD, and Patrick Ellinor, MD, PhD, of the CVRC. Support for the study includes National Institutes of Health grants NS084863, HL128264, HL114477, HL117829, HL092577, HL105780, and HL096576. The MGH has filed a patent application covering the work described in this paper.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $800 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2016 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of "America's Best Hospitals."
Journal
Cell