Probing single ventricle heart defects with patient‐derived induced pluripotent stem cells and emerging technologies

Abstract

Single ventricle heart defects (SVHDs) are a severe type of congenital heart disease with poorly understood pathogenic mechanisms. New research using patient‐specific induced pluripotent stem cells (iPSCs) as a cellular model is beginning to uncover genetic and cellular etiologies of SVHDs. Hypoplastic left heart syndrome (HLHS) is a type of SVHD that is characterized by an underdeveloped left ventricle and other malformations in the left side of the heart. Hypoplastic right heart syndrome (HRHS), the second type of SVHD, is characterized by an underdeveloped right heart, including malformed tricuspid and pulmonary valves. Despite a noticeable lack of research on SVHD, emerging technologies offer a promising future to further probe the genetic and cellular mechanisms of these diseases. Pediatric cardiovascular research is at the dawn of a new era in terms of what can be discovered with patient‐specific iPSCs in conjunction with other technologies (e.g., organoids, single‐cell genomics, CRISPR/Cas9 genome editing). In this review, we present recent approaches and findings utilizing patient‐specific iPSCs to identify cellular mechanisms responsible for improper cardiac organogenesis in HLHS and HRHS.

Narrative review of single ventricle: where are we after 40 years?

“…Rescuing a single ventricle in decompensated failure may also require the creation of new, functional myocardium (310). Because of these reasons, experimental studies on animals using stem cells have been conducted in various institutions, including a few clinical trials with progenitor stem cells given via direct myocardial injection or administration in the coronary arterial blood (311)(312)(313)(314)(315)(316)(317). The preservation of single ventricular function is the key for long-term outcomes, but currently the available methods to preserve or improve the myocardial function are still limited (314).…”

Generation of an induced pluripotent stem cell line NCHi003-A from a 11-year-old male with pulmonary atresia with intact ventricular septum (PA-IVS)

“…PA-IVS carries a significant risk of early morbidity and mortality that warrants immediate intervention after birth ( Rao, 2021 ; Wright et al, 2019 ). The cause of PA-IVS is poorly understood and patient cell-based experimental models are not available ( Hall et al, 2022 ). Here, an iPSC line was generated from the peripheral blood mononuclear cells (PBMCs) of a male patient with PA-IVS and verified to model stages of human development through differentiation into cells from the three germ layers.…”