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Induced Pluripotent Stem Cell–Based Modeling of Single-Ventricle Congenital Heart Diseases

  • Regenerative Medicine (SM Wu, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Congenital heart disease includes a wide variety of structural cardiac defects, the most severe of which are single ventricle defects (SVD). These patients suffer from significant morbidity and mortality; however, our understanding of the developmental etiology of these conditions is limited. Model organisms offer a window into normal and abnormal cardiogenesis yet often fail to recapitulate complex congenital heart defects seen in patients. The use of induced pluripotent stem cells (iPSCs) derived from patients with single-ventricle defects opens the door to studying SVD in patient-derived cardiomyocytes (iPSC-CMs) in a variety of different contexts, including organoids and chamber-specific cardiomyocytes. As the genetic and cellular causes of SVD are not well defined, patient-derived iPSC-CMs hold promise for uncovering mechanisms of disease development and serve as a platform for testing therapies. The purpose of this review is to highlight recent advances in iPSC-based models of SVD.

Recent Findings

Recent advances in patient-derived iPSC-CM differentiation, as well as the development of both chamber-specific and non-myocyte cardiac cell types, make it possible to model the complex genetic and molecular architecture involved in SVD development. Moreover, iPSC models have become increasingly complex with the generation of 3D organoids and engineered cardiac tissues which open the door to new mechanistic insight into SVD development. Finally, iPSC-CMs have been used in proof-of-concept studies that the molecular underpinnings of SVD may be targetable for future therapies.

Summary

While each platform has its advantages and disadvantages, the use of patient-derived iPSC-CMs offers a window into patient-specific cardiogenesis and SVD development. Advancement in stem-cell based modeling of SVD promises to revolutionize our understanding of the developmental etiology of SVD and provides a tool for developing and testing new therapies.

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Abbreviations

ASD:

Atrial septal defect

CHD:

Congenital heart disease

CM:

Cardiomyocyte

HLHS:

Hypoplastic left heart syndrome

iPSC:

Human-derived induced pluripotent stem cells

LV:

Left ventricle

PA/IVS:

Pulmonary atresia with intact ventricular septum

SVD:

Single-ventricle disease

RV:

Right ventricle

TA:

Tricuspid atresia

uAVCD:

Unbalanced atrioventricular canal defect

VSD:

Ventricular septal defect

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Funding

LP is supported by the Duke University School of Medicine Medical Scientist Training Program (T32-GM-145449–01). APL is supported by the National Institutes of Health (K08-HL136839 and R01-HL160654), Doris Duke Charitable Foundation (CSDA-2020098), and Additional Ventures.

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  1. Lauren E Parker and Leonie M Kurzlechner are co-equal first authors/contributed equally to the manuscript.

Authors and Affiliations

  1. Department of Pediatrics, Division of Cardiology, Duke University School of Medicine, Durham, NC, USA

    Lauren E. Parker, Leonie M. Kurzlechner & Andrew P. Landstrom

  2. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA

    Andrew P. Landstrom

  3. Duke University Medical Center, Box 2652, Durham, NC, 27710, USA

    Andrew P. Landstrom

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  1. Lauren E. Parker
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Parker, L.E., Kurzlechner, L.M. & Landstrom, A.P. Induced Pluripotent Stem Cell–Based Modeling of Single-Ventricle Congenital Heart Diseases. Curr Cardiol Rep 25, 295–305 (2023). https://doi.org/10.1007/s11886-023-01852-3

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