Cells lining the heart indicate the size of the heart — ScienceDaily

About one percent of the world’s population is born with a congenital heart defect, which affects approximately 40,000 births in the United States each year, but how these particular 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) have determined that the cells that line the heart direct the heart muscle to grow. until the heart reaches its maximum size. They also described 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 go wrong 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 understand how to regenerate the heart. Currently, no one can regenerate an entire heart, mainly because they have focused on using the heart muscle to develop more heart muscle cells,” Deqiang said. Li, PhD, assistant professor of surgery at the University of Maryland School of Medicine in the Center for Vascular and Inflammatory Diseases. “Our results suggest that we may need other cells in the heart, such as the epicardium (the cells that line the heart), to provide the necessary instructions for heart muscle to grow.”

The mechanism described by the team was published on June 20 in Traffic research.

The gene regulatory histone deacetylase 3 (HDAC3, for short) was known to be important for the development of heart muscle cells, but whether it plays a specific role in the separate layer of cells that line the heart was unknown. To explore the role of HDAC3 in heart development, researchers genetically engineered mice to only lack HDAC3 in the cells that line the heart. In fetal mice, they found that those hearts without HDAC3 in the lining of the heart had thinner, more compact walls in the ventricles of the heart – basically, it looked like the hearts weren’t growing enough.

The research team determined that cells lining the heart without the HDAC3 gene regulator also produced fewer of the two growth factors that these cells normally pump to promote heart growth, while producing too many of two microRNAs. MicroRNAs are small pieces of genetic material that control which genes are turned on and turned into proteins.

“We struggled to put the pieces of this mechanism together for a long time. One day, postdoctoral fellow and lead author of the study, Jihyun Jang, PhD, approached me and expressed the brilliant idea of ​​double braking microRNAs preventing growth factors from being made, which ultimately turned out to be true!” said Dr. Li. We could not have completed this study without the valuable contributions and insights of our co-authors, as well as the support of the Department of Surgery and the Center for Vascular and Inflammatory Diseases. »

Separately, they found that HDAC3 turns off the genes that code for the two microRNAs, allowing growth factors to be generated and ensuring the heart reaches normal size.

“You might be wondering, why use such a complicated strategy that requires crossing two double brakes for a normal heart to develop? Well, gene regulators like HDAC3 are found in every cell in the body, and microRNAs are also found everywhere.These specific regulators “Obstacles allow this process to be specialized in various places in the body. Of course, this also means that these cellular mechanisms may also have applications for other diseases, such as cancer,” Dr. Li said. “To some people, this mechanism and these findings may seem incredibly detailed. If you think about life, the details matter. If one little thing goes wrong, then everything goes wrong.”

E. Albert Reece, MD, PhD, MBA, Vice President for Medical Affairs, University of Maryland, and John Z. and Akiko K. Bowers Professor Emeritus and Dean, University of Maryland School of Medicine, said: “One of the health conditions I’ve spent much of my career studying is the mechanisms that cause structural birth defects. Basic research, such as that done in this study, is essential for us to know how the body develops normally, so that we can determine what is wrong with disease, and eventually one day, if so, we can find ways to prevent congenital heart defects in the next generation of newborns. »

Other authors include visiting postdoctoral researcher Guang Song, MD, PhD; lab technician Sarah Pettit; Postdoctoral Fellow Qinshan Li, MD, PhD; Visiting Student Xiaosu Song, MD, PhD; and Sunjay Kaushal, PhD, MD, professor of surgery, all from 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 start-up funds from the Department of Surgery, University of Maryland School of Medicine.