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      Development of a primary human Small Intestine-on-a-Chip using biopsy-derived organoids

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          Abstract

          Here we describe a method for fabricating a primary human Small Intestine-on-a-Chip (Intestine Chip) containing epithelial cells isolated from healthy regions of intestinal biopsies. The primary epithelial cells are expanded as 3D organoids, dissociated, and cultured on a porous membrane within a microfluidic device with human intestinal microvascular endothelium cultured in a parallel microchannel under flow and cyclic deformation. In the Intestine Chip, the epithelium forms villi-like projections lined by polarized epithelial cells that undergo multi-lineage differentiation similar to that of intestinal organoids, however, these cells expose their apical surfaces to an open lumen and interface with endothelium. Transcriptomic analysis also indicates that the Intestine Chip more closely mimics whole human duodenum in vivo when compared to the duodenal organoids used to create the chips. Because fluids flowing through the lumen of the Intestine Chip can be collected continuously, sequential analysis of fluid samples can be used to quantify nutrient digestion, mucus secretion and establishment of intestinal barrier function over a period of multiple days in vitro. The Intestine Chip therefore may be useful as a research tool for applications where normal intestinal function is crucial, including studies of metabolism, nutrition, infection, and drug pharmacokinetics, as well as personalized medicine.

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          Most cited references 36

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          NIH Image to ImageJ: 25 years of image analysis.

          For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the analysis of scientific images. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.
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            Organoids as an in vitro model of human development and disease.

            The in vitro organoid model is a major technological breakthrough that has already been established as an essential tool in many basic biology and clinical applications. This near-physiological 3D model facilitates an accurate study of a range of in vivo biological processes including tissue renewal, stem cell/niche functions and tissue responses to drugs, mutation or damage. In this Review, we discuss the current achievements, challenges and potential applications of this technique.
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              The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations.

              The small intestine epithelium undergoes rapid and continuous regeneration supported by crypt intestinal stem cells (ISCs). Bmi1 and Lgr5 have been independently identified to mark long-lived multipotent ISCs by lineage tracing in mice; however, the functional distinctions between these two populations remain undefined. Here, we demonstrate that Bmi1 and Lgr5 mark two functionally distinct ISCs in vivo. Lgr5 marks mitotically active ISCs that exhibit exquisite sensitivity to canonical Wnt modulation, contribute robustly to homeostatic regeneration, and are quantitatively ablated by irradiation. In contrast, Bmi1 marks quiescent ISCs that are insensitive to Wnt perturbations, contribute weakly to homeostatic regeneration, and are resistant to high-dose radiation injury. After irradiation, however, the normally quiescent Bmi1(+) ISCs dramatically proliferate to clonally repopulate multiple contiguous crypts and villi. Clonogenic culture of isolated single Bmi1(+) ISCs yields long-lived self-renewing spheroids of intestinal epithelium that produce Lgr5-expressing cells, thereby establishing a lineage relationship between these two populations in vitro. Taken together, these data provide direct evidence that Bmi1 marks quiescent, injury-inducible reserve ISCs that exhibit striking functional distinctions from Lgr5(+) ISCs and support a model whereby distinct ISC populations facilitate homeostatic vs. injury-induced regeneration.
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                Author and article information

                Contributors
                david.breault@childrens.harvard.edu
                don.ingber@wyss.harvard.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                13 February 2018
                13 February 2018
                2018
                : 8
                Affiliations
                [1 ]ISNI 000000041936754X, GRID grid.38142.3c, Wyss Institute for Biologically Inspired Engineering at Harvard University, ; Boston, MA 02115 USA
                [2 ]ISNI 0000 0001 2156 2780, GRID grid.5801.c, Graduate program, Department of Health Sciences and Technology, ETH Zurich, ; Zurich, Switzerland
                [3 ]GRID grid.5963.9, Graduate program, Faculty of Biology, , University of Freiburg, ; Freiburg, Germany
                [4 ]ISNI 0000 0001 2181 4263, GRID grid.9983.b, Graduate program, Department of Bioengineering and iBB - Institute for Bioengineering and Biosciences, , Instituto Superior Técnico, Universidade de Lisboa, ; Lisboa, Portugal
                [5 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Department of Molecular Pharmacology and Experimental Therapeutics, , Mayo Clinic College of Medicine, ; Rochester, MN 55905 USA
                [6 ]ISNI 0000 0004 0378 8438, GRID grid.2515.3, Division of Endocrinology, , Boston Children’s Hospital, ; Boston, MA 02115 USA
                [7 ]ISNI 0000 0004 0378 8438, GRID grid.2515.3, Division of Gastroenterology, , Boston Children’s Hospital, ; Boston, MA 02115 USA
                [8 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Pediatrics, , Harvard Medical School, ; Boston, MA 02115 USA
                [9 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard Stem Cell Institute, , Harvard University, ; Boston, MA 02139 USA
                [10 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard John A. Paulson School of Engineering and Applied Sciences, , Harvard University, ; Cambridge 02139, MA USA
                [11 ]ISNI 0000 0004 0378 8438, GRID grid.2515.3, Vascular Biology Program and Department Surgery, , Boston Children’s Hospital and Harvard Medical School, ; Boston 02115, MA USA
                [12 ]Present Address: Emulate Inc., 27 Drydock Avenue, Boston, MA 02210 USA
                Article
                21201
                10.1038/s41598-018-21201-7
                5811607
                29440725
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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