An iPSC-derived small intestine-on-chip with self-organizing epithelial, mesenchymal, and neural cells
Renée Moerkens,
Joram Mooiweer,
Aarón D. Ramírez-Sánchez,
Roy Oelen,
Lude Franke,
Cisca Wijmenga,
Robert J. Barrett,
Iris H. Jonkers,
Sebo Withoff
Affiliations
Renée Moerkens
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
Joram Mooiweer
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
Aarón D. Ramírez-Sánchez
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
Roy Oelen
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Lude Franke
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Cisca Wijmenga
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
Robert J. Barrett
Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; F. Widjaja Foundation Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
Iris H. Jonkers
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
Sebo Withoff
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands; Corresponding author
Summary: Human induced pluripotent stem cell (hiPSC)-derived intestinal organoids are valuable tools for researching developmental biology and personalized therapies, but their closed topology and relative immature state limit applications. Here, we use organ-on-chip technology to develop a hiPSC-derived intestinal barrier with apical and basolateral access in a more physiological in vitro microenvironment. To replicate growth factor gradients along the crypt-villus axis, we locally expose the cells to expansion and differentiation media. In these conditions, intestinal epithelial cells self-organize into villus-like folds with physiological barrier integrity, and myofibroblasts and neurons emerge and form a subepithelial tissue in the bottom channel. The growth factor gradients efficiently balance dividing and mature cell types and induce an intestinal epithelial composition, including absorptive and secretory lineages, resembling the composition of the human small intestine. This well-characterized hiPSC-derived intestine-on-chip system can facilitate personalized studies on physiological processes and therapy development in the human small intestine.
