Al Green sang it best when he crooned the words, “How can you mend a broken heart? How can you stop the rain from falling down?”
While scientists have yet to figure out how to absolve heartbreak, they have made steps towards regenerating heart muscle. The cells that make up this tissue are known as cardiomyocytes. In adult mammals, these cells have little ability to proliferate. Unlike external skin cells and the cells lining the inner cardiovascular vessels, which are continuously being replenished, the cells of the heart do not have regenerative ability. Since heart disease and heart failure are such widespread diseases in our country, an important scientific effort centers around stimulating heart cells to regenerate and help repair damage.
Regeneration has been shown only during the first week of life for mammalian hearts. During formation of the heart, a protein called neuregulin-1 binds to cardiomyocyte receptors in the ERBB family. This protein is critical for the proper development of the heart. Imagine that the cardiomyocytes represent the door to a house. The ERBB receptor is the lock on the door, and the protein neuregulin-1 is the key that perfectly fits into that lock. When the lock and key fit, they help foster proper development of the heart. When this protein binds to its receptor, a process known as signaling occurs, allowing cells to appropriately receive, interpret, and respond to a message.
Image Source: Derek Croucher
Decreased levels of neuregulin-1 signaling have been associated with adverse cardiac functioning, while injection of this protein into adult mice after heart injury has been associated with improved cardiovascular functioning. As this protein is thought to cause improvement after interacting with the ERBB receptor, researchers in this study looked at one of the ERBB family members: ERBB2. However, they found that ERBB2 doesn’t bind to any signaling molecules, such as neuregulin-1, but it binds instead to other ERBB family members. ERBB2 can be thought of as the nails connecting the lock to the door, strengthening and stabilizing the actual “lock”, enabling it to do its job. Without ERBB2, a weaker binding of neuregulin-1 to the ERBB receptor would lead to lower levels of downstream cell signaling.
These studies, which were published in Nature, demonstrated that ERBB2 is necessary to allow heart cell proliferation upon treatment with neuregulin-1. After the first week of life in mammals, reduced levels of ERBB2 are available in the cardiomyocytes. However, overexpression of the gene that encodes for ERBB2 caused notable enlargement in the heart, with evident cardiomyocyte proliferation. Kind of similar to when the Grinch’s heart grew three sizes that one Christmas Day in How the Grinch Stole Christmas. Additionally, temporary expression of the ERBB2 gene in mice stimulated cardiomyocyte proliferation and allowed regeneration of the heart after injury.
This exciting finding demonstrates that controlling neuregulin-1 signaling through ERBB2 could serve as a therapeutic means of treating patients with heart failure. Since this neuregulin-ERBB2 signaling pathway is limited after the first week of life, activation of ERBB2 after this period appears to promote cardiomyocyte division. In essence, the induction of ERBB2 essentially “reverses” them to a younger state, enabling them to behave as they would during the first week of life.
Further studies are needed to successfully translate these findings into a clinical therapy for heart failure patients. However, this study serves as a major advancement in the field of regenerative medicine.
