Cardiomyocyte research reveals new way to regenerate damaged heart cells

Scientists at Northwestern Medicine have discovered a way to regenerate damaged heart muscle cells in mice, which could open a new way to treat congenital heart defects in children and heart damage after heart attacks in adults, according to a study published in Journal of Clinical Investigation.

Hypoplastic left heart syndrome (HLHS) is a rare congenital heart defect that occurs when the left side of a baby's heart does not develop properly during pregnancy, reports Ann & Robert H. Lurie Children's Hospital of Chicago. The condition affects one in 5,000 newborns and is responsible for 23% of deaths from heart disease in the first week of life.

Cardiomyocytes, the cells responsible for contracting the heart muscle, can regenerate in newborn mammals but lose this ability as they age, said Paul Shumaker, Ph.D., professor of pediatrics in the department of neonatology and senior author of the study.

"At birth, heart muscle cells may still be undergoing mitotic division," Schumaker said. "For example, if the heart of a newborn mouse is damaged at one or two days of age, and then you wait until the mouse is an adult, when you examine the damaged area of the heart, you will never know that there was damage there."

In the current study, Shumaker and colleagues sought to understand whether adult mammalian cardiomyocytes can revert to a fetal regenerative state.

Because fetal cardiomyocytes survive on glucose instead of generating cellular energy through their mitochondria, Schumaker and colleagues deleted a mitochondria-related gene, UQCRFS1, in the hearts of adult mice, causing them to revert to a fetal-like state.

In adult mice with damaged heart tissue, the researchers observed that heart cells began to regenerate after UQCRFS1 was inhibited. The cells also began to consume more glucose, similar to how fetal heart cells function, according to the study.

The study results suggest that increasing glucose use can also restore cell division and growth in adult heart cells and may provide a new direction for treating damaged heart cells, Shumaker said.

"This is the first step toward solving one of the most important questions in cardiology: how do we get heart cells to divide again so we can repair hearts?" said Shumaker, who is also a professor of cell and developmental biology and medicine in the department of pulmonary and critical care medicine.

Based on this discovery, Shumaker and his colleagues will focus on identifying drugs that can induce this response in heart cells without genetic modification.

"If we can find a drug that turns on this response in the same way as a genetic modification, we can then remove the drug once the heart cells have grown," Shumaker said. "In children with HLHS, this may allow us to restore normal left ventricular wall thickness. This could be life-saving."

This approach can also be used for adults who have suffered a heart attack, Shumaker said.

"This has been a great project and I am grateful to everyone involved," Shumaker said. "The paper listed 15 Northwestern faculty members as co-authors, so it was truly a team effort."