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Unique Cellular Trajectories Result in Reduced Cardiomyocyte Proliferation Capacities in Single Ventricle Disease

Unique Cellular Trajectories Result in Reduced Cardiomyocyte Proliferation Capacities in Single Ventricle Disease 1024 537 Jessica Nye, PhD

Cellular trajectories deviate early in hypoplastic left heart syndrome (HLHS) and hypoplastic right heart syndrome (HRHS) development.

Hypoplastic left and right heart syndromes are two rare and distinct single ventricle heart defects which are the most severe subtypes of congenital heart disease, usually requiring prompt surgical intervention after birth.

“Clinically, there are large differences between hypoplastic left and hypoplastic right [heart syndromes]. But their mechanisms and disease etiologies have previously been almost impossible to study, because after the baby is born, you cannot trace back to what’s happening during heart development,” says Ming-Tao Zhao, DVM, PhD, principal investigator in the Center for Cardiovascular Research at Nationwide Children’s Hospital and an associate professor at The Ohio State University.

In a study published in the European Heart Journal, Dr. Zhao and colleagues developed patient-specific induced pluripotent stem cell (iPSC) lines from 3 patients with HLHS and 3 with HRHS. Each iPSC line had a paired control cell line derived from an unaffected family member of the same sex. The proliferation capacity, gene expression profile and single-cell RNA sequencing data from HLHS-cardiomyocytes (CMs) and HRHS-CMs were compared between syndromes and their respective genetic background control.

The investigators observed that CMs derived from HLHS and HRHS had decreased proliferation capacities relative to CMs from paired controls (all P = 0.05). In addition, the gene expression profiles of HLHS and HRHS differed from controls by having lower expression of genes associated with cell cycle regulation and higher expression of genes associated with cardiac structure and function.

Mingtao Zhao, DVM, PhD

“We found that although they share common mechanisms, such as cardiomyocyte proliferation defects, we were surprised that during early stages of the heart development, they show different developmental trajectories,” says Dr. Zhao.

Next, Dr. Zhao and colleagues tracked the CM developmental processes through day 30. At day 10, they observed that the epicardial cell lineage progenitor was overrepresented at the cost of the first and second heart field cell lineage progenitors in HLHS whereas the first heart field cell lineage progenitor was expanded, and the second heart field cell lineage progenitor was contracted in HRHS development.

At day 14, the HRHS iPSC-CMs were found to have higher reactive oxygen species generation and elevated DNA damage compared with controls (all P= 0.05).At day 30, HLHS iPSC-CMs had reduced oxygen consumption and ATP production (all P = 0.05) while HRHS iPSC-CMs had increased oxygen consumption and ATP production (all P= 0.01) relative to controls.

Overall, these findings indicate that heart field progenitors and cell metabolism were differentially disrupted in HLHS and HRHS, ultimately leading to similar reductions in CM proliferation capacities.

Dr. Zhao concludes, “We have created multiple iPSC lines from single ventricle diseases, including hypoplastic left and right [heart syndromes]. We have created a resource that will be available, not only to investigators at Nationwide Children’s Hospital, but also available to the larger single ventricle research community in the US. Because Nationwide Children’s is one of the largest children’s hospitals in the nation, we can recruit enough patients to generate these iPSC lines, as the iPSC model is the only available model for single ventricle disease.”

Dr. Yang Yu, a postdoctoral fellow in Dr. Zhao’s lab is the lead author of this study. Vidu Garg, MD, and Karen Texter, MD, in The Heart Center at Nationwide Children’s Hospital contributed to recruitment of patients with HLHS and HRHS. Qin Ma, PhD and his group in the Department of Biomedical Informatics at The Ohio State University College of Medicine led the data analysis of single-cell sequencing. This study was funded by the Additional Ventures, National Institutes of Health and the American Heart Association.

 

Reference:

Yu Yang, Wang C, Ye S, Qin H, Alonzo M, Onorato A, Argall A, Texter K, Ma Q, Garg V, Zhao M-T. Common and divergent cellular aetiologies underlying hypoplastic left heart syndrome and hypoplastic right heart syndrome. Eur Heart J. 2025:ehaf121.

About the author

Jessica Nye, PhD, is a freelance science and medical writer based in Barcelona, Spain. She completed her BS in biology and chemistry and MS in evolutionary biology at Florida State University. Dr. Nye studied population genetics for her doctorate in biomedicine at University of Pompeu Fabra. She conducted her postdoctoral research on the inheritance of complex traits at the Autonomous University of Barcelona.

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