About one percent of the world’s population is born with a congenital heart defect, which affects about 40,000 births in the US each year, but how these specific birth defects arise is largely unknown.
In an effort to learn more about how the heart develops, researchers at the University of Maryland School of Medicine (UMSOM) determined that the cells that line the heart direct the heart muscle to grow until the heart reaches its full size. . They also outlined the complex mechanism that regulates this process, which involves bypassing two sets of brakes for the heart to develop properly.
The researchers say these findings explain a little more about what can go wrong during development that can lead to heart birth defects and also help develop better techniques for regenerating heart tissue.
To recover from an illness, you need to figure out how to perform heart regeneration. Right now, no one can regenerate an entire heart, especially since they’ve focused on using the heart muscle to grow more heart muscle cells. Our findings suggest that we may need other cells of the heart, such as the epicardium (the cells that line the heart), to provide the necessary instructions for the heart muscle to enlarge.”
Deqiang Li, PhD, assistant professor of surgery at the University of Maryland School of Medicine in the Center for Vascular & Inflammatory Diseases
The mechanism the team described was published on June 20 in Circulation research.
The gene regulator histone deacetylase 3 (HDAC3) was known to be important for development in cardiac muscle cells, but whether it played a specific role in the individual layer of cells lining the heart was unknown. To investigate the role of HDAC3 in heart development, the researchers genetically engineered mice to lack HDAC3 only in the cells that line the heart. In fetal mice, they found that these hearts without HDAC3 in the lining had thinner, compact walls in the ventricles — in fact, it seemed like the hearts weren’t growing enough.
The research team found that the cells lining the heart without the gene regulator HDAC3 also made less of the two growth factors that these cells normally pump out to stimulate heart growth, while also producing too much of two microRNAs. MicroRNAs are small pieces of genetic material that determine which genes are turned on and made into proteins.
“We were struggling for a long time to put the pieces together for this mechanism. One day, postdoctoral fellow and lead study author Jihyun Jang, PhD, approached me and expressed the brilliant idea of double inhibition mechanisms of the microRNAs that prevent the growth factors be made, which in the end turned out to be true!” said Dr. Li. “We could not have completed this study without valuable contributions and insights from our co-authors, as well as support from the Department of Surgery and the Center for Vascular and Inflammatory Diseases.”
Separately, they found that HDAC3 knocks out genes encoding the two microRNAs, allowing the generation of the growth factors and ensuring the heart grows to full size.
“You may ask, why would you use such a complicated strategy that requires two double brakes to develop a normal heart? Well, gene regulators like HDAC3 are found in every cell in the body, and microRNAs are also found everywhere. These specific regulatory hurdles allow this process to specialize to different sites in the body, which of course means that these cell mechanisms may also have applications for other diseases, such as cancer,” said Dr. Li. “To some people, this mechanism and these findings can seem incredibly detailed. However, when you think about life, details matter. When one little thing goes wrong, everything goes wrong.”
E. Albert Reece, MD, PhD, MBA, Vice President of Medical Affairs, University of Maryland, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine, said, “One of the health concerns Conditions I’ve studied for much of my career are the mechanisms behind structural birth defects. Basic research, as conducted in this study, is essential for us to figure out how the body develops normally so we can determine what’s going wrong in disease, and eventually in this case we may one day find ways to prevent congenital heart defects in the next generation of newborns.”
University of Maryland School of Medicine
Jang, J., et al. (2022) Epicardial HDAC3 promotes myocardial growth through a novel microRNA pathway. Circulation research. doi.org/10.1161/CIRCRESAHA.122.320785.