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Coordinated differentiation of human intestinal organoids with functional enteric neurons and vasculature.
Cell Stem Cell
March 2025
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, USA; Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Biomedical Engineering, University of Michigan and University of Michigan College of Engineering, Ann Arbor, MI, USA. Electronic address:
Human intestinal organoids (HIOs) derived from human pluripotent stem cells co-differentiate both epithelial and mesenchymal lineages in vitro but lack important cell types such as neurons, endothelial cells, and smooth muscle, which limits translational potential. Here, we demonstrate that the intestinal stem cell niche factor, EPIREGULIN (EREG), enhances HIO differentiation with epithelium, mesenchyme, enteric neuroglial populations, endothelial cells, and organized smooth muscle in a single differentiation, without the need for co-culture. When transplanted into a murine host, HIOs mature and demonstrate enteric nervous system function, undergoing peristaltic-like contractions indicative of a functional neuromuscular unit.
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