Qiu YX, Zhi ZK, Leng YM, Zhang XT, Du CX, Tang J, Li HX, Tang WB. Induced pluripotent stem cells in Hirschsprung disease: Modeling, mechanisms, and translational challenges. World J Stem Cells 2026; 18(8): 123046 [DOI: 10.4252/wjsc.123046]
Corresponding Author of This Article
Hong-Xing Li, MD, PhD, Associate Professor, Department of Pediatric Surgery, Children’s Hospital of Nanjing Medical University, No. 72 Guangzhou Road, Nanjing 210008, Jiangsu Province, China. hx8817@njmu.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
review-article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Stem Cells. Aug 26, 2026; 18(8): 123046 Published online Aug 26, 2026. doi: 10.4252/wjsc.123046
Induced pluripotent stem cells in Hirschsprung disease: Modeling, mechanisms, and translational challenges
Yuan-Xiang Qiu, Zheng-Ke Zhi, Yu-Mu Leng, Xin-Tao Zhang, Chun-Xia Du, Jie Tang, Hong-Xing Li, Wei-Bing Tang
Yuan-Xiang Qiu, Zheng-Ke Zhi, Xin-Tao Zhang, Chun-Xia Du, Jie Tang, Hong-Xing Li, Wei-Bing Tang, Department of Pediatric Surgery, Children’s Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu Province, China
Yu-Mu Leng, Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
Co-first authors: Yuan-Xiang Qiu and Zheng-Ke Zhi.
Co-corresponding authors: Hong-Xing Li and Wei-Bing Tang.
Author contributions: Qiu YX and Zhi ZK contributed equally to this manuscript as co-first authors. Qiu YX and Zhi ZK performed the literature search, analyzed the data, and drafted and revised the manuscript; Leng YM was responsible for data visualization and the creation of figures; Zhang XT assisted with literature collection and data verification; Du CX assisted in data sorting and manuscript proofreading; Tang J participated in result collation and logical revision of the manuscript; Li HX and Tang WB contributed equally to this manuscript as co-corresponding authors. Li HX and Tang WB supervised the project, were responsible for funding acquisition, and critically revised the manuscript for important intellectual content. All authors have read and approved the final manuscript.
AI contribution statement: ChatGPT (OpenAI) was used as an assistive tool for language polishing, translation, and writing support in portions of the authors’ responses to the reviewers. The entirety of the responses was not AI-generated. All scientific content, interpretation of evidence, responses to reviewer comments, manuscript revisions, and final wording were independently reviewed, verified, and approved by the authors. AI tools were not used to generate original scientific data, perform independent scientific analyses, or draw scientific conclusions. The authors take full responsibility and accountability for all content of this manuscript, including any portions for which ChatGPT was used as an assistive technology.
Supported by the National Natural Science Foundation of China, No. 82001590 and No. 82270540.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Hong-Xing Li, MD, PhD, Associate Professor, Department of Pediatric Surgery, Children’s Hospital of Nanjing Medical University, No. 72 Guangzhou Road, Nanjing 210008, Jiangsu Province, China. hx8817@njmu.edu.cn
Received: May 11, 2026 Revised: June 17, 2026 Accepted: July 13, 2026 Published online: August 26, 2026 Processing time: 102 Days and 15.8 Hours
Abstract
Hirschsprung disease (HSCR) is a congenital disorder of the enteric nervous system (ENS) caused by impaired migration, proliferation, survival, and differentiation of enteric neural crest cells (ENCCs) during intestinal development. Although many HSCR-associated genes and regulatory variants have been identified, most cases are oligogenic or multifactorial, and mechanistic studies are limited by scarce human embryonic enteric tissues. Patient-derived induced pluripotent stem cells (iPSCs) preserve individual genetic backgrounds and can be differentiated into ENCCs, enteric neurons, and intestinal or colonic organoids, providing human platforms for modeling early ENS development and disease-relevant phenotypes. This review summarizes iPSC platform establishment, ENCC differentiation, two-dimensional ENCC models, recombined or co-culture organoids, emerging bioengineered gut systems, drug screening, and regenerative strategies. We discuss how genetic complexity, isogenic controls, multi-omics integration, electrophysiological maturation, and ENCC-microenvironment interactions influence model interpretation. Current applications remain limited by developmental immaturity, inter-line and inter-batch variability, incomplete functional validation, safety concerns, manufacturing requirements, and pediatric regulatory considerations. At present, iPSC-based HSCR models are best viewed as complementary tools for mechanistic investigation and preclinical development rather than direct routes to clinical therapy.
Core Tip: Patient-derived induced pluripotent stem cell (iPSC) platforms provide human models for linking Hirschsprung disease (HSCR)-associated genetic backgrounds with enteric neural crest cell (ENCC) developmental phenotypes and tissue-level interactions. This review summarizes iPSC platform establishment, two-dimensional ENCC models, recombined and bioengineered gut systems, drug screening, and cell-based regenerative strategies. We emphasize genetic complexity, reproducibility, functional maturation, electrophysiological validation, and translational feasibility. Current iPSC-based HSCR models are most useful for mechanistic investigation and preclinical development, whereas drug screening and cell therapy remain exploratory.
