{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T02:44:44Z","timestamp":1778035484623,"version":"3.51.4"},"reference-count":252,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T00:00:00Z","timestamp":1757116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"British Heart Foundation","award":["PG\/15\/11\/31279"],"award-info":[{"award-number":["PG\/15\/11\/31279"]}]},{"name":"British Heart Foundation","award":["PG\/15\/86\/31723"],"award-info":[{"award-number":["PG\/15\/86\/31723"]}]},{"name":"British Heart Foundation","award":["PG\/20\/10458"],"award-info":[{"award-number":["PG\/20\/10458"]}]},{"name":"British Heart Foundation","award":["PG\/23\/11371"],"award-info":[{"award-number":["PG\/23\/11371"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease affecting 2\u20133 neonates every 10,000 live births. While prior research has highlighted associations of HLHS with specific chromosomal abnormalities and genetic mutations, the precise pathophysiology remains elusive. Despite early surgical intervention potentially allowing most HLHS patients to survive their critical heart disease with a single-ventricle physiology, patients frequently experience complications of arrhythmias and right ventricular heart failure, culminating in the need for an eventual heart transplant. Scarcity of suitable donors combined with limited understanding of mechanisms of development highlights the need for furthering our understanding of HLHS and alternative treatment options. Over the past decades, stem cell research has significantly advanced our understanding of cardiac conditions, repair, development, and therapy, opening the door for a new exciting field of regenerative medicine in cardiology with significant implications for HLHS. This review serves to provide a comprehensive overview of a much focused-on area related to HLHS. Specifically, we will first discuss the key pathophysiological basis and signalling molecules of HLHS. We then outline the emerging role of stem cell-based therapy, with a focus on adult stem cells and pluripotent stem cells (PSCs) in uncovering the pathophysiology of HLHS and optimising future treatment directions. Finally, we will also explore the latest and possible future directions of stem cell-derived techniques such as cardiac organoids and bioengineering cardiac tissues and their utility for investigating disease mechanisms, drug screening, and novel therapy for HLHF.<\/jats:p>","DOI":"10.3390\/cells14171396","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T08:06:32Z","timestamp":1757318792000},"page":"1396","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Updated Applications of Stem Cells in Hypoplastic Left Heart Syndrome"],"prefix":"10.3390","volume":"14","author":[{"given":"Rui","family":"Xiao","sequence":"first","affiliation":[{"name":"Norfolk and Norwich University Hospital NHS Foundation Trust, Colney Ln, Norwich NR4 7UY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haleema","family":"Darr","sequence":"additional","affiliation":[{"name":"University Hospital Coventry and Warwickshire, Clifford Bridge Rd, Coventry CV2 2DX, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zarif","family":"Khan","sequence":"additional","affiliation":[{"name":"University College London Hospital NHS Foundation Trust, 250 Euston Road, London NW1 2PG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9101-0498","authenticated-orcid":false,"given":"Qingzhong","family":"Xiao","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2301","DOI":"10.1002\/bdr2.2301","article-title":"National population-based estimates for major birth defects, 2016\u20132020","volume":"116","author":"Stallings","year":"2024","journal-title":"Birth Defects Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/j.jacc.2011.09.022","article-title":"Hypoplastic left heart syndrome: Current considerations and expectations","volume":"59","author":"Feinstein","year":"2012","journal-title":"J. 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