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A Noncardiomyocyte Signaling Pathway in Early Heart Development

A Noncardiomyocyte Signaling Pathway in Early Heart Development 1024 670 Mary Bates, PhD

Study demonstrates role for endocardial cells in myocardial trabeculation.

A new study in Nature Communications from researchers at Nationwide Children’s Hospital provides novel insights into a signaling pathway that regulates the developing myocardium during early heart development. The findings have implications for understanding congenital heart disease and myocardial regeneration.

This research was led by Deqiang Li, PhD, and Jihyun Jang, PhD, both principal investigators, who teamed up with Vidu Garg, MD, director of the Center for Cardiovascular Research and the Nationwide Foundation Endowed Chair in Cardiovascular Research, in the Abigail Wexner Research Institute (AWRI) at Nationwide Children’s. Key collaborators include Mario Looso, PhD, at Max Planck Institute, Germany, and Chen-Leng Cai, PhD, at Indiana University School of Medicine.

Congenital heart disease (CHD) is the most common congenital disorder, and the leading cause of mortality from birth defects. Yet, there remain many questions about how and why heart defects develop in some children and not others, says Deqiang Li, MD, PhD, a principal investigator in the Center for Cardiovascular Research at Nationwide Children’s and senior author of the study.

Deqiang Li, PhD

“Many genes and signaling pathways work together in an elegant and precise manner to form a heart,” he says. “The process is challenging to study.”

Several forms of CHD are associated with abnormal development of the ventricular chambers, which pump blood to the lungs and body, and cardiac trabeculation is a critical step in early heart development involving the compaction of spongy muscle fiber networks to become a smooth and solid ventricular wall. Proper trabeculation depends on contributions from both cardiomyocytes and non-cardiomyocyte cells, such as cardiac endothelial cells (CECs, also called endocardial cells). CECs influence trabeculation by secreting extracellular matrix and growth factors; however, it is not well understood how developing CECs initiate and regulate these secretions.

Epigenetic modulators, such as enzymes called histone deacetylases (HDACs), play an important role in early heart development by regulating gene expression. Recently, Dr. Li and colleagues demonstrated that epicardial HDAC3 is critical for driving myocardial compact wall expansion.

In the new study, the team investigated the role of endocardial HDAC3 in myocardial trabeculation. Dr. Li and colleagues conducted several in vivo and in vitro experiments with mouse models, in which they selectively knocked out HDAC3 in the developing myocardium.

The researchers found that specific deletion of HDAC3 in the endocardium resulted in hypotrabeculation (decreased trabecular cardiomyocyte proliferation) and early embryo lethality. Investigating further, they found that endocardial HDAC3 stimulates cardiomyocyte proliferation and promotes myocardial trabeculation by inducing signaling of a growth factor called transforming growth factor β (TGFβ). But HDAC3 does not impact TGFβ directly; the results showed that HDAC3 induces TGFβ signaling through repressing a specific microRNA (miR-129-5p).

“This work provides new information on one way in which myocardial growth can be regulated during early heart development,” says Dr. Li, who is also an associate professor in the Department of Pediatrics at The Ohio State University College of Medicine.

“Our findings demonstrate the importance of non-cardiomyocyte cells in driving myocardial development. They highlight the role of endocardial signaling in regulating myocyte proliferation and myocardial trabeculation.”

 

Reference:

Jang J, Bentsen M, Kim YJ, Kim E, Garg V, Cai C-L, Looso M, Li D. Endocardial HDAC3 is required for myocardial trabeculation. Nature Communications. 2024;15:4166.

About the author

Mary a freelance science writer and blogger based in Boston. Her favorite topics include biology, psychology, neuroscience, ecology, and animal behavior. She has a BA in Biology-Psychology with a minor in English from Skidmore College in Saratoga Springs, NY, and a PhD from Brown University, where she researched bat echolocation and bullfrog chorusing.

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