Embryonic microRNA fuels heart cell regeneration, Temple researchers show

(Philadelphia, PA) – By adulthood, the heart is no longer able to replenish injured or diseased cells. As a result, heart disease or an event like a heart attack can be disastrous, leading to massive cell death and permanent declines in function. A new study by scientists at the Lewis Katz School of Medicine at Temple University (LKSOM), however, shows that it may be possible to reverse this damage and restore heart function, even after a severe heart attack.

The study, published June 21 in the print edition of the journal Circulation Research, is the first to show that a very small RNA molecule known as miR-294, when introduced into heart cells, can reactivate heart cell proliferation and improve heart function in mice that have suffered the equivalent of a heart attack in humans.

“In previous work, we discovered that miR-294 actively regulates the cell cycle in the developing heart,” said Mohsin Khan, PhD, Assistant Professor of Physiology at the Center for Metabolic Disease Research at LKSOM. “But shortly after birth miR-294 is no longer expressed.”

Dr. Khan and colleague Raj Kishore, PhD, Professor of Pharmacology and Medicine and Director of the Stem Cell Therapy Program in the Center for Translational Medicine at LKSOM, both senior investigators on the new study, wondered whether miR-294 could serve as a sort of fountain of youth for heart cells.

“The heart is very proliferative when miR-294 is expressed in early life,” Dr. Kishore explained. “We wanted to see if reintroducing it into adult heart cells would turn them back to an embryonic-like state, allowing them to make new heart cells.”

The researchers tested their idea in mice that had myocardial infarction (heart attack). Mice were treated with miR-294 continuously for two weeks after sustaining myocardial injury. Two months following treatment, the researchers observed noticeable improvements in heart function and a decrease in the area of damaged tissue. Examination of treated heart cells revealed evidence of cell cycle reentry, indicating that the cells had been reactivated, regaining the ability to produce new cells.

“The miR-294 treatment reawakened an embryonic signaling program in the adult heart cells,” said Dr. Khan. “Because of this, the old heart cells were no longer quite like adult cells, but neither were they fully embryonic. In this in-between state, however, they had the ability to make new cells.”

The researchers were able to control miR-294 expression, turning it on or off and thereby dictating the amount of proliferative activity in the heart.

Drs. Khan and Kishore plan next to replicate the study in a large animal model. They also want to gain a deeper understanding of what miR-294 is doing in the heart. “There is evidence that it does more than control the cell cycle,” Dr. Khan said. “If it has multiple targets, we need to find them.”

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Other researchers involved in the study include Austin Borden and Justin Kurian, Center for Metabolic Disease Research, LKSOM; Yijun Yang, Sadia Mohsin, Constantine Troupes, and Steven R. Houser, Cardiovascular Research Center, LKSOM; Jessica Ibetti, Anna Maria Lucchese, Erhe Gao, and Walter J. Koch, Center for Translational Medicine, LKSOM; and Emily Nickoloff, Department of Pharmacology and Physiology, Drexel University College of Medicine.

The research was funded by National Institutes of Health grants HL135177, HL091983, HL126186 and HL134608 and American Heart Association Scientific Development Grant 15SDG22680018.

About Temple Health

Temple University Health System (TUHS) is a $2.1 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the “Best Hospitals” in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with the Lewis Katz School of Medicine at Temple University, and Temple University Physicians, which is Temple Health’s physician practice plan comprised of more than 500 full-time and part-time academic physicians in 20 clinical departments.

The Lewis Katz School of Medicine (LKSOM), established in 1901, is one of the nation’s leading medical schools. Each year, the School of Medicine educates more than 800 medical students and approximately 240 graduate students. Based on its level of funding from the National Institutes of Health, the Katz School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, LKSOM is among the top 10 most applied-to medical schools in the nation.

Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System (TUHS) and by the Katz School of Medicine. TUHS neither provides nor controls the provision of health care. All health care is provided by its member organizations or independent health care providers affiliated with TUHS member organizations. Each TUHS member organization is owned and operated pursuant to its governing documents.