Newswise – About one percent of the world’s population is born with a congenital heart defect, which affects about 40,000 births in the United States each year, but exactly how these birth defects occur 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 cells lining the heart direct the heart muscle to grow until the heart reaches its full size. They also identified the complex mechanism that regulates this process, which requires bypassing two sets of brakes for the heart to develop properly.
The researchers say these findings explain a little more about what can happen during development that can lead to congenital heart defects and may also help develop better techniques for regenerating heart tissue.
“To recover from disease, you need to know how to do heart regeneration. At this time, no one can regenerate an entire heart, mostly because they have focused on using heart muscle to grow more heart muscle cells,” Deqiang Li, Ph.D.And the Associate Professor of Surgery at the University of Maryland School of Medicine in the Center for Vascular and Inflammatory Diseases. “Our findings suggest that we may need other cells from the heart, such as the epicardium (cells lining the heart), to give the instructions needed for cardiac muscle growth.”
The mechanism described by the team was published on 20 June Circulation Research.
The regulator gene histone deacetylase 3 (HDAC3, for short) has been known to be important for development in cardiomyocytes, but whether or not it plays a specific role in the detached layer of cells lining the heart has been known. To explore the role of HDAC3 in heart development, researchers genetically engineered mice so that they lack HDAC3 only in the cells lining the heart. In fetal mice, they found that those hearts without HDAC3 in the lining of the heart had thinner compressed walls in the ventricles of the heart—basically, the hearts did not seem to grow sufficiently.
The research team determined that cells lining the heart without the HDAC3 gene regulator also produced less of the two growth factors that these cells normally pump out to encourage heart growth, while also producing more of the two microRNAs. MicroRNAs are small pieces of genetic material that control which genes are turned on and turned into proteins.
“We’ve been struggling to piece the pieces together of this mechanism for a long time. One day, my postdoc fellow and lead study author Jihyun Jang, Ph.D., approached me and expressed the brilliant idea of the dual-repressing mechanisms of microRNAs that prevent the formation of growth factors, which In the end it turned out to be true!” Dr. Lee said. “We would not have been able to complete 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 turns off the genes encoding two microRNAs, allowing the formation of growth factors and ensuring that the heart grows to full size.
“You might ask, why would you use such a complex strategy that requires going through a double brake to get a normal heart to develop? Well, genetic regulators like HDAC3 are found in every cell in the body, and microRNAs are also everywhere. These specific regulatory hindrances allow this process to specialize In different places in the body. Of course, this also means that these cell mechanisms may have applications for other diseases, such as cancer,” said Dr. Lee. “To some people, this mechanism and these findings may seem incredibly detailed. If you think about life, the details matter. If one small mistake goes wrong, everything screws up.”
E. Albert Reis, MD, PhD, MBAD., Vice President for Medical Affairs, University of Maryland, Distinguished Professor John Z. and Akiko K. Bowers and Dean of the University of Maryland School of Medicine, said: “One health condition that I have spent most of my career studying is the mechanisms behind skeletal birth defects. The primary research, Like what was done in this study, it’s essential for us to know how the body develops normally, so that we can determine what’s wrong with the disease, and eventually one day, in this case, we can find ways to prevent congenital heart defects in The next generation of newborns.”
Additional authors include Visiting Postdoctoral Fellow Gwang Song, MD, PhD; lab technician Sarah Pettit; Postdoctoral Fellow Qinshan Li, MD, Ph.D.; Visiting Student Xiao Song, MD, PhD; Sunjay Kaushal, MD, MD, professor of surgery, University of Maryland School of Medicine; and Chen-leng Cai, Ph.D., of Indiana University.
This work was supported by the National Heart, Lung, and Blood Institute (grant R01HL153406) and start-up 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 College of Medicine was accredited in 1807 as the first general medical school in the United States. It continues today as one of the world’s fastest growing and highest-caliber biomedical research institutions – with 46 academic departments, centers, institutes and programs, a panel of more than 3,000 physicians, scientists, and allied health professionals, including members from the National Academy of Medicine and the National Academy of Sciences, and a two-time Distinguished Winner Albert E. Lasker Award in Medical Research. With an operating budget of more than $1.3 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and the Medical System to provide extensive research, academic, and clinical care to nearly two million patients each year. The medical school has approximately $600 million in external funding, with most of its academic departments ranking highly among all medical schools in the country in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore Campus, the medical school has a population of nearly 9,000 faculty and staff, including 2,500 students, interns, residents, and fellows. The Combined College of Medicine and Medical System (“University of Maryland Medicine”) has a budget of more than $6 billion and an economic impact of nearly $20 billion on the state and community. Faculty of Medicine, which is classified as 8 top Among the public medical schools in research productivity (according to the profile of the Association of American Medical Colleges) is an innovator in transformational medicine, with 606 active patents and 52 start-ups. in the last US News & World Report Ranking of Best Medical Schools, published in 2021, UM Medical School is Rank No. 9 Among the 92 general medical colleges In the United States, in the top 15 percent (No. 27) out of 192 general and personal American Medical Colleges. The School of Medicine works locally, nationally, and globally with research and treatment facilities in 36 countries around the world. visit medschool.umaryland.edu