Induced pluripotent stem cells in Hirschsprung disease: Modeling, mechanisms, and translational challenges

Table 1 Comparison of induced pluripotent stem cell-based and emerging gut modeling platforms relevant to Hirschsprung disease research

Comparison domain	2D iPSC-derived ENCC models	3D recombined/co-culture organoid models	Emerging integrated/bioengineered platforms
Model design	ENCCs or enteric neurons in monolayer culture	Gut organoids combined with ENCCs	Integrated organoids, de novo innervated tissues, or gut-on-chip systems
HSCR-specific validation	Relatively established	Moderate	Limited
Main use	Cell-autonomous defects and candidate gene testing	ENCC colonization and tissue-level interaction	Dynamic multicellular interaction and future translational modeling
Reproducibility/scalability	Relatively high; scalable	Moderate to low; less scalable	Variable; technically demanding
Physiological relevance	Low to moderate	Moderate to high	Potentially high, but not yet validated in HSCR
Functional/drug-screening value	Migration, proliferation, differentiation, early compound testing	Neuromuscular patterning, calcium activity, contractile response	Barrier function, flow, mechanical cues, exploratory testing
Major limitations	Lacks tissue context and mature ENS function	Batch variability and incomplete maturation	High cost, low throughput, limited HSCR-specific evidence

2D: Two-dimensional; iPSC: Induced pluripotent stem cell; ENCC: Enteric neural crest cell; 3D: Three-dimensional; HSCR: Hirschsprung disease; ENS: Enteric nervous system.