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Full text release has been delayed at the author's request until April 25, 2026

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Elucidating Pathological Alterations in Coronary Endothelium and Valve Cells in Single Ventricle Disease

Yu, Zhiyun
http://orcid.org/0000-0001-6568-9978
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1721640780615201

Abstract Details

2024, PhD, University of Cincinnati, Medicine: Cancer and Cell Biology.
Congenital heart disease (CHD) stands as the most prevalent congenital anomaly, impacting approximately 4 per 1000 live births. Single ventricle (SV) CHD, constituting 7.7% of CHDs, represents a severe and intricate form of CHD where patients typically exhibit a single dominant left or right ventricle at birth, insufficient to sustain normal pulmonary and systemic circulation. SV CHDs encompass diverse cardiac malformations, including semilunar (SL) or atrioventricular (AV) valve hypoplasia, stenosis/atresia, and malalignment of the pulmonary artery and aorta. The varied manifestations of SV abnormalities imply a complex disease etiology intertwined with various cardiac developmental anomalies. Despite substantial progress in understanding the molecular mechanisms of various SV diseases, intrinsic defects in human cardiac endothelium and related valvular structures remain elusive. The advent of single-cell RNA sequencing (scRNA-seq) has revolutionized our ability to precisely dissect cellular identity, functions, and interactions during cardiogenesis and CHD pathogenesis. Leveraging human induced pluripotent stem cells (iPSCs) expands our experimental repertoire, allowing the generation of various cardiac cell types to functionally validate genomic and transcriptomic data in cellular models. Herein, we combined scRNA-seq analysis of human tissues with patient-derived iPSCs to unravel the endothelial/valvular pathobiology in SV diseases, such as hypoplastic left heart syndrome (HLHS) and pulmonary stenosis (PS). The effort extended to specify iPSC-derived valve endothelial cells (VECs) and valve interstitial cells (VICs) representing the specificity of all four valves. Despite the previous knowledge of myocardial defects in HLHS pathology, we demonstrated the intrinsic defect in disease vascular arterial endothelium, including KMT2D-NOTCH mediated proliferation, angiogenesis, and EC-smooth muscle cell interactions. Our results suggested the importance of vascular endothelium function in promoting HLHS pathogenesis, providing new angles for treatment. To better understand the cellular composition and behavior of human valve endothelium and its derivative VICs during normal valve development and the disease progression of PS, we analyzed the single-cell transcriptome of VECs and VICs from two fetal hearts and a heart with PS at gestation day 105. We underscored the crucial role of VEC-VIC crosstalk in affecting elastin fiber fragmentation in the PS pulmonary valve through Jag1-NOTCH, emphasizing again the important function of valve endothelium in valve homeostasis. Finally, instructed by the distinct transcriptomes of VECs from four valves, we developed the iPSC differentiation platform to generate iPSC-VECs resembling SL-VECs derived from the anterior second heart field and AV-VECs derived from the posterior second heart field at the fetal stage. Our results showed the great promise of investigating the PV-specific VEC and VIC phenotypes in vitro by using patient-derived iPSCs. Taken together, our studies unveiled various defects in coronary AECs in HLHS and pulmonary valve elastin fiber assembly in PS, deepened our understanding of endothelial/valvular pathobiology in SV CHDs. Our exploration of in vitro approaches to generate four valve-specific EECs from iPSCs opened a new venue to investigate disease cellular phenotypes of specific valves.
Mingxia Gu, M.D. Ph.D. (Committee Chair)
Susanne Wells, Ph.D. (Committee Member)
Mei Xin, Ph.D. (Committee Member)
Katherine Yutzey, Ph.D. (Committee Member)
Yanbo Fan, Ph.D. (Committee Member)
171 p.
Biology
induced pluripotent stem cell; congenital heart disease; coronary vascular; endothelial cell; valve development; NOTCH

Recommended Citations

Citations

  • Yu, Z. (2024). Elucidating Pathological Alterations in Coronary Endothelium and Valve Cells in Single Ventricle Disease [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1721640780615201

    APA Style (7th edition)

  • Yu, Zhiyun. Elucidating Pathological Alterations in Coronary Endothelium and Valve Cells in Single Ventricle Disease. 2024. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1721640780615201.

    MLA Style (8th edition)

  • Yu, Zhiyun. "Elucidating Pathological Alterations in Coronary Endothelium and Valve Cells in Single Ventricle Disease." Doctoral dissertation, University of Cincinnati, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1721640780615201

    Chicago Manual of Style (17th edition)

ucin1721640780615201
© 2024, some rights reserved.Creative Commons License Elucidating Pathological Alterations in Coronary Endothelium and Valve Cells in Single Ventricle Disease by Zhiyun Yu is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.