Stem Cell Study Opens Door to Understanding Development of Rare Form of Congenital Heart Disease

Stem Cell Study Opens Door to Understanding Development of Rare Form of Congenital Heart Disease 150 150 Pam Georgiana

Researchers use induced pluripotent stem cell technology and single-cell genomics to pinpoint abnormal cell development in hypoplastic right heart syndrome.

A rare form of hypoplastic right heart syndrome (HRHS), pulmonary atresia with intact ventricular septum (PA-IVS), occurs when the structures on the right side of the heart are malformed. Specifically, in PA-IVS, the pulmonary valve does not open, resulting in no connection between the heart’s right ventricle and pulmonary arteries. Further, PA-IVS is associated with right ventricular hypoplasia, which is characterized by the underdevelopment or inadequate growth of the right ventricle. This condition is often a complex congenital heart defect and can impact the heart’s ability to pump blood effectively. Without cardiac intervention as a neonate, PA-IVS is lethal.

Recently, Mingtao Zhao, PhD, assistant professor in the Center for Cardiovascular Research at Nationwide Children’s, teamed up with Vidu Garg, MD, director of the Center for Cardiovascular Research and the Nationwide Foundation Endowed Chair in Cardiovascular Research, and Karen Texter, MD, director of the single ventricle program in the Heart Center at Nationwide Children’s to study the biological factors contributing to HRHS. Other collaborators include Qin Ma, PhD, professor in the Department of Biomedical Informatics at The Ohio State University College of Medicine, and Samir Ghadiali, PhD, professor and chair in the Department of Biomedical Engineering at The Ohio State University College of Engineering. The results were recently published in Circulation.

Specifically, the team was interested in learning more about the process of cardiomyocyte proliferation during embryonic heart development in HRHS. Cardiomyocytes are specialized cells that form the heart muscle. They are responsible for the contraction and relaxation of the heart, allowing it to pump blood throughout the body. With induced pluripotent stem cell (iPSC) technology, scientists can take cells from a patient with heart disease and reprogram them to iPSCs in a lab to study them further.

“This technology is exciting because there are no reproducible models to study the causes of single ventricle heart defects. We can recreate the development phases of a heart that contains all a patient’s genetic content in a lab,” Dr. Zhao says.

The team recruited PA-IVS patients from The Heart Center at Nationwide Children’s to create a panel of patient-specific iPSCs. These patient-specific cells can be reprogrammed to have the characteristics of human embryonic stem cells and then differentiated into various cardiac cell types. Single-cell RNA-sequencing technology can then be used to discover cellular and molecular deficits

“We wanted to study what happened to the heart cells in this patient population at each stage of development. We included family members of the patients as a control group to factor out other genetic variables,” Dr. Zhao explains.

The team found a variety of defects in the iPSC-derived cardiac cells. For example, the patients had a lower percentage of proliferating cardiomyocytes compared to controls. The cells also displayed less proliferation under cyclic stretch conditions.

“Stretching normally increased the proliferation of heart cells, as we saw in the control cells. However, our study found that this wasn’t always true in patients with PA-IVS,” Dr. Garg says.

Also, the number of Second Heart Field (SHF) progenitors, or cells that contribute to the formation of the heart, was dramatically diminished in PA-IVS patients compared to controls. Since SHF primarily contributes to the development of the right ventricle, this finding may be a critical factor in the development of PA-IVS.

“In the simplest of terms, second heart field cells are supposed to contribute to the heart’s right ventricle and pulmonary valve. Instead, in these patients, the SHF cells were not differentiating properly, potentially contributing to the heart defect at birth,” Dr. Garg explains.

The researchers conclude that the combination of compromised cardiomyocyte proliferation and a depreciated amount of SHF cells could be a reason why right ventricular hypoplasia develops. However, due to limitations in the technology, which was 2D, Drs. Zhao and Garg stress that further study using new 3D technology to develop cardiac organoids is necessary to uncover more details about how heart defects develop.

“The new 3D technology has the potential to allow us to better understand how the human heart develops. Accordingly, we’ll be able to identify the molecular deficits that result in heart defects using patient-specific cells. Ultimately, if we can understand why congenital heart defects occur, we can develop new therapies to treat patients with these severe forms of heart disease,” Dr. Garg says.



Yu Y, Wang C, Ye S, et al. Abnormal Progenitor Cell Differentiation and Cardiomyocyte Proliferation in Hypoplastic Right Heart Syndrome. Circulation. 2024;149(11):888-891. doi:10.1161/CIRCULATIONAHA.123.064213

About the author

Pam Georgiana is a brand marketing professional and writer located in Bexley, Ohio. She believes that words bind us together as humans and that the best stories remind us of our humanity. She specialized in telling engaging stories for healthcare, B2B services, and nonprofits using classic storytelling techniques. Pam has earned an MBA in Marketing from Capital University in Columbus, Ohio.