Coordinated differentiation of human intestinal organoids with functional enteric neurons and vasculature
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. HIOs also form functional vasculature, demonstrated in vitro using microfluidic devices and in vivo following transplantation, where HIO endothelial cells anastomose with host vasculature. These complex HIOs represent a transformative tool for translational research in the human gut and can be used to interrogate complex diseases as well as for testing therapeutic interventions with high fidelity to human pathophysiology.
Authors
- Zhiwei Xiao (ORCID: https://orcid.org/0000-0001-5522-2813)
- Rosemary Spencer (ORCID: https://orcid.org/0000-0002-9369-4472)
- Holly M. Poling (ORCID: https://orcid.org/0000-0002-3595-1944)
- Charlie J. Childs (ORCID: https://orcid.org/0000-0002-4480-2625)
- Roman J. Giger (ORCID: https://orcid.org/0000-0002-2926-3336)
- Yu-Hwai Tsai
- Angeline Wu (ORCID: https://orcid.org/0000-0003-2742-8296)
- Meghan F. Anderman (ORCID: https://orcid.org/0000-0002-6413-2745)
- Jason R. Spence (ORCID: https://orcid.org/0000-0001-7869-3992)
- Caden W. Sweet
- Akaljot Singh (ORCID: https://orcid.org/0000-0001-6925-2968)
- Maxime M. Mahé (ORCID: https://orcid.org/0000-0003-2560-193X)
- Jonathan Villanueva (ORCID: https://orcid.org/0000-0002-1789-6822)
- S Paris
- Michael A. Helmrath (ORCID: https://orcid.org/0000-0003-3112-7541)
- Claudia Loebel (ORCID: https://orcid.org/0000-0002-3140-5663)
- Ryan Schreiner
- Madeline K. Eiken (ORCID: https://orcid.org/0000-0002-2162-7422)
- Emily M. Holloway (ORCID: https://orcid.org/0000-0001-9893-1265)
- Sha Huang (ORCID: https://orcid.org/0000-0001-8419-0320)
- Abigail Vallie
- Ansley S. Conchola (ORCID: https://orcid.org/0000-0002-2385-6712)
- Shahin Rafii (ORCID: https://orcid.org/0000-0001-5605-1067)
- Kevin Yanjun Chen (ORCID: https://orcid.org/0000-0002-3851-6016)
- Katherine D. Walton (ORCID: https://orcid.org/0000-0001-9108-5617)
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Inserm (FR)
- California Institute for Regenerative Medicine (US)
- Cornell University (US)
- University of Michigan (US)
- The Enteric Nervous System in Gut and Brain Disorders (FR)
- Weill Cornell Medicine (US)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- Cell stem cell
- Published
- 2025-03-04
- DOI
- https://doi.org/10.1016/j.stem.2025.02.007
- Citations
- 27
- Primary Topic
- Digestive system and related health
- Type
- article
- Field-Weighted Citation Impact
- 49.07
Funders
- Chan Zuckerberg Initiative
- National Institute of Diabetes and Digestive and Kidney Diseases