Therapeutic strategies capable of repairing the heart stand to revolutionize the treatment of heart disease. Reaching that goal, however, requires extensive knowledge of the cellular mechanisms that drive responses to heart injuries, such as heart attack. Now, with the renewal of a $12 million Program Project Grant (PPG) from the National Heart, Lung, and Blood Institute (NHLBI), scientists at the Lewis Katz School of Medicine at Temple University are able to more deeply explore novel mechanisms of heart injury and repair involving specific heart cell-derived microvesicles known as exosomes. The research could open new avenues in exosome-based treatments for heart tissue repair and regeneration.

The principal investigator on the PPG renewal is Raj Kishore, PhD, Laura H. Carnell Professor and Chair of the Department of Cardiovascular Sciences and Professor in the Aging + Cardiovascular Discovery Center at the Katz School of Medicine. According to Dr. Kishore, “Every cell releases exosomes, but what each exosome carries differs. The focus of our new PPG is to figure out how injury to the heart alters exosome-mediated cell-cell communication, both locally within injured heart tissue and distally with other organs, such as adipose and bone marrow.”

The PPG renewal builds on work funded in 2017 by an $11.6 million dollar NHLBI PPG awarded to Dr. Kishore. Studies during the initial PPG established the utility of stem cell-derived exosomes as a promising therapeutic modality for post-injury heart repair and cast light on mechanisms by which stem cell-derived exosomes exert their effects.

Exosomes, which are roughly 50-150 nanometers in diameter, mediate cell-cell communication. Following their secretion by donor cells, they are taken up by neighboring and distant cells and release their cargo, which includes cell-specific small RNAs and proteins. Once delivered to recipient cells, exosome cargo alters the biology and function of the recipient cell. These changes determine the response to injury.

“Intracellular and inter-organ communication by exosomes influences how the heart responds to injury,” Dr. Kishore explained.

Many heart injuries result in substantial damage from ischemia – a sudden, severe blockage of blood flow to heart tissue. Recovery from ischemia requires extensive cellular restoration and tissue regrowth. The mechanisms by which cardiac cell-derived exosomes drive these disease and repair processes, however, remains largely unknown.

To find out, three projects were devised by Dr. Kishore and colleagues Walter Koch, PhD, Professor of Cardiovascular and Thoracic Surgery at Duke University, and Douglas Tilley, PhD, Professor of Cardiovascular Sciences in the Aging + Cardiovascular Discovery Center. The new award further supports two scientific cores, one led by Dr. Kishore and the second by John Elrod, PhD, Director of the Aging + Cardiovascular Discovery Center and Professor of Cardiovascular Sciences at the Katz School of Medicine.

Dr. Kishore’s project will examine the role of exosomes derived from stressed heart muscle cells, with attention to understanding the role of specific microRNAs in the restoration of heart cell function and blood vessel regeneration.

“We are interested especially in how exosomes facilitate crosstalk between cells in the heart and in the vasculature,” he explained. “We suspect that specific molecules, such as microRNAs, are central to these communication pathways.”

Dr. Koch’s team will work toward elucidating signaling pathways in heart stem cells that involve exosomes containing G-coupled receptor kinase-2 (GRK2). GRK2 potentially serves a function in exosome communication between adipose tissue and heart cells.

The third project, led by Dr. Tilley, seeks to identify ways to enhance immune cell-mediated cardiac repair, how existing therapeutics alter these processes, and whether immune cell-derived exosomes can be engineered to improve outcomes following cardiac injury.

“Drs. Kishore, Koch, and Elrod are exceptional colleagues and team players,” Dr. Tilley said. “I can't be more excited about our growing scientific program over the next five years, [thanks to the PPG renewal].”

“The renewal of the PPG allows us to build on our initial investigations into whether stem cell-derived exosomes are a therapeutically viable approach for heart repair following heart attack,” Dr. Kishore noted. “Now we can focus on better understanding how injured cells communicate with other cells throughout the body and how this impacts the heart’s response to injury.”

“The groundbreaking work of Dr. Kishore and his team promises to unlock new understanding of heart repair mechanisms, potentially transforming therapeutic strategies for heart disease,” said Amy J. Goldberg, MD, FACS, The Marjorie Joy Katz Dean at the Katz School of Medicine. “We are proud of the collaborative spirit and innovative science that this grant supports, reinforcing our position at the forefront of medical research.”

“The continuation of Dr. Kishore’s PPG is a testament to the collaborative environment and high-impact science being performed at the Lewis Katz School of Medicine,” Dr. Elrod said. “In total, the Aging + Cardiovascular Discovery Center has been home to five PPGs over the last decade, including the two led by Dr. Kishore. These prestigious multi-investigator grants provide tangible evidence of the cooperation and collegiality among our scientists.”

“Applying for this type of funding is extremely competitive,” Dr. Koch added. “Dr. Kishore’s leadership was essential to the process of securing the PPG renewal, which will allow our programs to reach new heights in the area of cardiac signaling and repair.”