Newswise – 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 disease, you have to figure out how to do heart regeneration. Right now, no one can regenerate a whole heart, especially because they’ve focused on using the heart muscle to grow more heart muscle cells,” said Deqiang Li, PhD, assistant professor of surgery at the University of Maryland School of Medicine in the Center for Vascular & Inflammatory Diseases. “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.”
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 struggled for a long time to put together the pieces 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 from being 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 wonder why you would use such a complicated strategy where you have to use 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. mechanism and these findings seem incredibly detailed. However, when you think about life, details matter. If one little thing gets messed up, everything messes up.”
E. Albert Reece, MD, PhD, MBAVice President for 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 issues I’ve studied for much of my career is 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 that we can determine what goes wrong in disease, and eventually, one day, we may, in this case, find ways to treat congenital heart defects in the next generation of newborns.”
Other authors included Visiting Postdoctoral Fellow Guang Song, MD, PhD; Laboratory technician Sarah Pettit; Postdoctoral researcher Qinshan Li, MD, PhD; Visiting student Xiaosu Song, MD, PhD; and Sunjay Kaushal, PhD, MD, professor of surgery, all of the University of Maryland School of Medicine; and Chen-leng Cai, PhD, of Indiana University.
This work was supported by the National Heart, Lung, and Blood Institute (grant R01HL153406) and seed funds from the Department of Surgery, University of Maryland School of Medicine.
About the University of Maryland School of Medicine
Now in the third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. Today it remains one of the fastest growing, leading biomedical research companies in the world – with 46 academic departments, centers, institutes and programs, and a faculty of more than 3,000 physicians, scientists and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and two-time winner of the Albert E. Lasker Award in Medical Research. With an operating budget of more than $1.3 billion, the School of Medicine works closely with the University of Maryland Medical Center and Medical System to provide nearly 2 million patients with research-intensive, academic and clinically based care each year. The School of Medicine has nearly $600 million in outpatient funding, with most of its academic departments ranked highly among all medical schools in the nation in research funding. As one of seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, interns, residents, and fellows. The combined School of Medicine and Medical System (“University of Maryland Medicine”) has an annual budget of more than $6 billion and an economic impact of nearly $20 billion on the state and local community. The School of Medicine, which ranks as the 8th highest among public medical schools in research productivity (according to the profile of the Association of American Medical Colleges) is an innovator in translational medicine, with 606 active patents and 52 start-up companies. In the last US news and world report ranking of the Best Medical Schools, published in 2021, the UM School of Medicine is ranked #9 among the 92 public medical schools in the US, and in the top 15 percent (#27) of all 192 public and private American medical schools. The School of Medicine works locally, nationally and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu