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Stem Cell Reports. 2015 Jun 3. pii: S2213-6711(15)00122-8. doi: 10.1016/j.stemcr.2015.04.010. [Epub ahead of print]

Transcriptome-wide Analysis Reveals Hallmarks of Human Intestine Development and Maturation In Vitro and In Vivo.

Author information

1
Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
2
Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
3
Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
4
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
5
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
6
Department of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
7
Department of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of General Surgery, University of Cincinnati, Cincinnati, OH 45229, USA.
8
Institute for Human Genetics and Department of Pediatrics, University of California, San Francisco, San Franciso, CA 94143, USA.
9
Center for Systems and Synthetic Biology, University of California, San Francisco, San Franciso, CA 94143, USA.
10
Institute for Human Genetics and Department of Pediatrics, University of California, San Francisco, San Franciso, CA 94143, USA; Program in Craniofacial and Mesenchymal Biology, University of California, San Francisco, San Franciso, CA 94143, USA; Center for Craniofacial Anomalies, University of California, San Francisco, San Franciso, CA 94143, USA.
11
Department of Medicine Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX 77030, USA.
12
Department of Pediatrics, University of Colorado, Denver, CO 80204, USA.
13
Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: spencejr@umich.edu.

Abstract

Human intestinal organoids (HIOs) are a tissue culture model in which small intestine-like tissue is generated from 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. Our study also revealed that the intestinal stem cell marker OLFM4 is expressed at very low levels in fetal intestine and in HIOs, but is robust in adult crypts. We validated our findings using in vivo transplantation to show that HIOs become more adult-like after transplantation. Our study emphasizes important maturation events that occur in the intestine during human development and demonstrates that HIOs can be used to model fetal-to-adult maturation.

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