A scientific technique that rapidly increases the body's production of anti-inflammatory cells promoted healing from heart attacks in mice, according to a new study by investigators from the Smidt Heart Institute at Cedars-Sinai. Once adapted to treat humans, the technique could potentially be used to repair heart muscle damage after a heart attack and be applied to a variety of inflammatory disorders.
The investigators' findings were published in the peer-reviewed Journal of Clinical Investigation .
Heart attacks occur when the heart muscle is damaged by reduced blood flow from one or more arteries. They strike more than 800,000 people in the U.S. each year and are a leading cause of death. The new technique, as described in the study, addresses a major challenge to treating this disorder: uncontrolled inflammation.
"Thanks largely to medical advances, more than 90% of people in the U.S. survive their heart attacks," said Eduardo Marbán, MD, PhD , executive director of the Smidt Heart Institute at Cedars-Sinai and the study's senior author. "But a significant percentage of these patients suffer tissue damage when their immune systems overreact. This can trigger inflammation, which weakens the heart and raises the risk of heart failure."
To solve this problem, the study's investigators focused on increasing the body's supply of regulatory T-cells (Tregs), which modulate the immune system and help keep it from overreacting to injuries. A number of clinical trials involving various diseases have sought to accomplish this goal through a weekslong process of extracting these rare cells from a patient, expanding them in the laboratory and infusing them back into the patient. But this method is too slow to help in an acute crisis like a heart attack.
Cedars-Sinai investigators wondered: What if we could stimulate the body to boost its own production of Tregs? The new method that they developed achieves this goal in mice through infusions of extracellular vesicles that overexpress an RNA molecule called BCYRN1. Extracellular vesicles are small fluid-filled sacs containing bioactive substances that are secreted by cells and circulate in the bloodstream.
By performing laboratory experiments on human tissue samples, the investigators first discovered how BCYRN1 works to increase the number and activity of Treg cells. Acting on these findings, they infused extracellular vesicles containing overexpressed BCYRN1 into mice 15 minutes after the mice had heart attacks.
The data showed that mice that received the infusions had more Tregs in their hearts and sustained less cardiac tissue damage and inflammation from the heart attacks than did mice that did not receive such infusions. Their hearts also retained more of their pumping power.
"These results reveal the important role of BCYRN1 in reducing inflammation and damage from heart attacks," said Ke Liao, PhD, a project scientist in the Smidt Heart Institute at Cedars-Sinai and first author of the study. "They also validate the effectiveness of using extracellular vesicles to deliver these benefits in mice."
The extracellular vesicles used in the study were produced by cardiosphere-derived cells, or CDCs, which naturally contain high levels of BCYRN1. These progenitor cells, derived from human heart tissue, were developed by Marbán over many years of work.
"Although this Smidt Heart Institute study was performed on animals, its findings have the potential to generate new and exciting immunotherapies," said Jeffrey A. Golden, MD , director of the Burns and Allen Research Institute and executive vice dean for Research and Education at Cedars-Sinai. "These therapies could have applications not only for heart attacks but for lupus, organ transplant rejection and other human disorders."
Other Cedars-Sinai authors include: Jiayi Yu, Akbarshakh Akhmerov, Zahra Mohammadi Goldar, Liang Li, Weixin Liu, Natasha Anders and Ahmed G.E. Ibrahim.
Funding: KL was supported by a training grant from the National Heart, Lung, and Blood Institute (T32 HL116273). This work was funded by NIH (R01HL168296 to E.M.) and the California Institute for Regenerative Medicine (CIRM DISC2-14899 to K.L.). E.M. holds the Mark S. Siegel Family Foundation Distinguished Chair of the Cedars-Sinai Medical Center. JY was supported by Tsinghua University. We thank all other members of the Marbán Laboratory for their support, and the Cedars-Sinai Medical Center Flow Cytometry Core. We acknowledge the use of BioRender for the preparation of figures in this manuscript.
Conflict of interest: E. Marbán owns founder's equity in Capricor Therapeutics.
