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      Small intestinal stem cell identity is maintained with functional Paneth cells in heterotopically grafted epithelium onto the colon

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          Abstract

          To develop stem cell therapy for small intestinal (SI) diseases, it is essential to determine whether SI stem cells in culture retain their tissue regeneration capabilities. Fukuda et al. demonstrate that cultured murine SI epithelial organoids are able to reconstitute self-renewing epithelia in the colon. The SI-derived grafts maintain many features unique only to the SI. This study provides evidence that cultured adult SI stem cells could be a source for cell therapy of intestinal diseases, maintaining their identity along the gastrointestinal tract through an epithelium-intrinsic mechanism.

          Abstract

          To develop stem cell therapy for small intestinal (SI) diseases, it is essential to determine whether SI stem cells in culture retain their tissue regeneration capabilities. By using a heterotopic transplantation approach, we show that cultured murine SI epithelial organoids are able to reconstitute self-renewing epithelia in the colon. When stably integrated, the SI-derived grafts show many features unique only to the SI but distinct from the colonic epithelium. Our study provides evidence that cultured adult SI stem cells could be a source for cell therapy of intestinal diseases, maintaining their identity along the gastrointestinal tract through an epithelium-intrinsic mechanism.

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          Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.

          Toshiro Sato, Robert G J Vries, Hugo J. Snippert … (2009)
          The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5(+) stem cells at the bottoms of small-intestinal crypts. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5(+) stem cells can also initiate these cryptvillus organoids. Tracing experiments indicate that the Lgr5(+) stem-cell hierarchy is maintained in organoids. We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
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            Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium.

            Toshiro Sato, Daniel E. Stange, Marc Ferrante … (2011)
            We previously established long-term culture conditions under which single crypts or stem cells derived from mouse small intestine expand over long periods. The expanding crypts undergo multiple crypt fission events, simultaneously generating villus-like epithelial domains that contain all differentiated types of cells. We have adapted the culture conditions to grow similar epithelial organoids from mouse colon and human small intestine and colon. Based on the mouse small intestinal culture system, we optimized the mouse and human colon culture systems. Addition of Wnt3A to the combination of growth factors applied to mouse colon crypts allowed them to expand indefinitely. Addition of nicotinamide, along with a small molecule inhibitor of Alk and an inhibitor of p38, were required for long-term culture of human small intestine and colon tissues. The culture system also allowed growth of mouse Apc-deficient adenomas, human colorectal cancer cells, and human metaplastic epithelia from regions of Barrett's esophagus. We developed a technology that can be used to study infected, inflammatory, or neoplastic tissues from the human gastrointestinal tract. These tools might have applications in regenerative biology through ex vivo expansion of the intestinal epithelia. Studies of these cultures indicate that there is no inherent restriction in the replicative potential of adult stem cells (or a Hayflick limit) ex vivo. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
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              Identification of stem cells in small intestine and colon by marker gene Lgr5.

              Nick Barker, Johan H van Es, Jeroen Kuipers … (2007)
              The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above the Paneth cells in the small intestine; colon stem cells remain undefined. Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5, also known as Gpr49) was selected from a panel of intestinal Wnt target genes for its restricted crypt expression. Here, using two knock-in alleles, we reveal exclusive expression of Lgr5 in cycling columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-lacZ reporter strain, lineage-tracing experiments were performed in adult mice. The Lgr5-positive crypt base columnar cell generated all epithelial lineages over a 60-day period, suggesting that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Genes Dev
                Journal ID (iso-abbrev): Genes Dev
                Journal ID (hwp): genesdev
                Journal ID (pmc): genesdev
                Journal ID (publisher-id): GAD
                Title: Genes & Development
                Publisher: Cold Spring Harbor Laboratory Press
                ISSN (Print): 0890-9369
                ISSN (Electronic): 1549-5477
                Publication date (Print): 15 August 2014
                Volume: 28
                Issue: 16
                Pages: 1752-1757
                Affiliations
                [1 ]Department of Gastroenterology and Hepatology,
                [2 ]Research Center for Medical and Dental Sciences,
                [3 ]Department of Human Genetics and Disease Diversity,
                [4 ]Bioresource Research Center,
                [5 ]Department of Advanced Therapeutics for GI Diseases, Tokyo Medical and Dental University, 113-8519 Tokyo, Japan
                Author notes
                [6]

                These authors contributed equally to this study.

                Corresponding author: nakamura.gast@ 123456tmd.ac.jp
                Article
                Medline ID: 8711660
                DOI: 10.1101/gad.245233.114
                PMC ID: 4197962
                PubMed ID: 25128495
                SO-VID: 8488dadf-1b9e-42f8-a247-71e9e38f3851
                Copyright © © 2014 Fukuda et al.; Published by Cold Spring Harbor Laboratory Press
                License:

                This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Date received : 19 May 2014
                Date accepted : 23 July 2014
                Page count
                Pages: 6
                Categories
                Subject: Research Communication

                Keywords: small intestinal stem cell,transplantation,stem cell niche,paneth cell,regenerative medicine
                Data availability:
                Keywords: small intestinal stem cell, transplantation, stem cell niche, paneth cell, regenerative medicine

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