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Datasets and R scripts related to the manuscript "Transcriptome-wide analysis reveals hallmarks of human intestine development and maturation in vitro and in vivo."

#Transcriptome-wide analysis reveals hallmarks of human intestine development and maturation in vitro and in vivo.

Stacy R. Finkbeiner1,2, David R. Hill1, Matthew Taylor3, Yu-Hwai Tsai1, Alana Chin4, Christopher Altheim1, Carey L. Watson6 , Jennifer J. Freeman2,5, Roy Nattiv8, Matthew Thomson11, Ophir D. Klein8,9,10, Noah F. Shroyer12, Michael A. Helmrath6,7, Daniel H. Teitelbaum2,5, Peter J. Dempsey13, Jason R. Spence1,2,4,*

1Division of Gastroenterology, Department of Internal Medicine; 2Center for Organogenesis; 3Department of Molecualr and Integrative Physiology; 4Department of Cell and Developmental Biology; 5Department of Surgery, Section of Pediatric Surgery. University of Michigan Medical School, Ann Arbor, Michigan

6Department of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center; 7Department of General Surgery, University of Cincinnati, Cincinnati, Ohio.

8Institute for Human Genetics and Department of Pediatrics; 9Program in Craniofacial and Mesenchymal Biology; 10Center for Craniofacial Anomalies; 11Center for systems and Synthetic Biology, University of California San Francisco San

12Department of Medicine Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas

13Department of Pediatrics, University of Colorado, Denver, Colorado.

*Author for correspondence: spencejr@umich.edu

Summary Human intestinal organoids (HIOs) are a tissue culture model of small intestine-like tissue that is generated through directed differentiation of pluripotent stem cells. Recent studies have suggested that HIOs are immature; however, it was unclear if HIOs represented tissue that was fetal-like, or alternatively, if expression levels of some genes simply remained low in vitro. We examined these possibilities further by using whole transcriptome gene expression comparisons between HIOs, human fetal and human adult gastrointestinal tissues. Our results show that HIOs most closely resemble human fetal intestine. This approach allowed us to elucidate cellular and molecular hallmarks of fetal-to-adult maturation in the human intestine. We found that genes involved in digestive tract development are enriched in HIOs and fetal tissue compared to adult tissue whereas genes related to digestive function and Paneth cell host-defense genes are found at much higher levels of expression in the adult intestine. Surprisingly, we also found that the intestinal stem cell marker OLFM4 is expressed at very low levels in fetal intestine and HIOs and that acquisition of strong OLFM4 expression is a hallmark of intestinal maturation. We validated our findings using in vivo transplantation to show that hallmarks of fetal-to-adult maturation are recapitulated as HIOs become adult-like after transplantation. In sum, our studies highlight major maturation events that occur in the intestine during human development and also demonstrate that HIOs are and in vitro model most closely resembling human fetal small intestine.

Abstract Human intestinal organoids (HIOs) are a three-dimensional tissue culture model in which small intestine-like tissue is generated through directed differentiation of pluripotent stem cells. By carrying out unsupervised hierarchical clustering of RNA-sequencing data, we demonstrate that HIOs most closely resemble human fetal intestine. We observed that genes involved in digestive tract development are enriched in both fetal intestine and HIOs compared to adult tissue, whereas genes related to digestive function and Paneth cell host-defense are expressed at higher levels in adult intestine. Surprisingly, our studies also revealed an unexpected finding that the intestinal stem cell marker OLFM4 is expressed at very low levels in fetal intestine and in HIOs. We validated our findings using in vivo transplantation to show that HIOs become more adult-like after transplantation. Our studies emphasize important maturation events that occur in the intestine during human development and demonstrate that HIOs can be used as a model of fetal small intestine.

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Datasets and R scripts related to the manuscript "Transcriptome-wide analysis reveals hallmarks of human intestine development and maturation in vitro and in vivo.""

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