Zinc Transporter SLC39A7/ZIP7 Promotes Intestinal Epithelial Self-Renewal by Resolving ER Stress

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Abstract

Zinc transporters play a critical role in spatiotemporal regulation of zinc homeostasis. Although disruption of zinc homeostasis has been implicated in disorders such as intestinal inflammation and aberrant epithelial morphology, it is largely unknown which zinc transporters are responsible for the intestinal epithelial homeostasis. Here, we show that Zrt-Irt-like protein (ZIP) transporter ZIP7, which is highly expressed in the intestinal crypt, is essential for intestinal epithelial proliferation. Mice lacking Zip7 in intestinal epithelium triggered endoplasmic reticulum (ER) stress in proliferative progenitor cells, leading to significant cell death of progenitor cells. Zip7 deficiency led to the loss of Olfm4 ⁺ intestinal stem cells and the degeneration of post-mitotic Paneth cells, indicating a fundamental requirement for Zip7 in homeostatic intestinal regeneration. Taken together, these findings provide evidence for the importance of ZIP7 in maintenance of intestinal epithelial homeostasis through the regulation of ER function in proliferative progenitor cells and maintenance of intestinal stem cells. Therapeutic targeting of ZIP7 could lead to effective treatment of gastrointestinal disorders.

Author Summary

Intestinal epithelium undergoes continuous self-renewal to maintain intestinal homeostasis. Given that dysregulation of zinc flux causes intestinal disorders, appropriate spatiotemporal regulation of zinc in the intracellular compartments should be a prerequisite for the intestinal epithelial self-renewal process. Zinc transporters such as Zrt-Irt-like proteins (ZIPs) are essential to fine-tune intracellular zinc flux. However, the link between specific zinc transporter(s) and intestinal epithelial self-renewal remains to be elucidated. Here, we found that ZIP7 is highly expressed in the intestinal crypts. The finding motivated us to further analyze the role of ZIP7 in intestinal homeostasis. ZIP7 deficiency greatly enhanced ER stress response in proliferative progenitor cells, which induced apoptotic cell death. This abnormality disrupted epithelial proliferation and intestinal stemness. Based on these observations, we reason that ZIP7-dependent zinc transport facilitates the vigorous epithelial proliferation in the intestine by ameliorating ER stress.

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Hua Tian, Brian Biehs, Søren Warming … (2011)

The small intestine epithelium renews every 2 to 5 days, making it one of the most regenerative mammalian tissues. Genetic inducible fate mapping studies have identified two principal epithelial stem cell pools in this tissue. One pool consists of columnar Lgr5-expressing cells that cycle rapidly and are present predominantly at the crypt base. The other pool consists of Bmi1-expressing cells that largely reside above the crypt base. However, the relative functions of these two pools and their interrelationship are not understood. Here we specifically ablated Lgr5-expressing cells in mice using a human diphtheria toxin receptor (DTR) gene knocked into the Lgr5 locus. We found that complete loss of the Lgr5-expressing cells did not perturb homeostasis of the epithelium, indicating that other cell types can compensate for the elimination of this population. After ablation of Lgr5-expressing cells, progeny production by Bmi1-expressing cells increased, indicating that Bmi1-expressing stem cells compensate for the loss of Lgr5-expressing cells. Indeed, lineage tracing showed that Bmi1-expressing cells gave rise to Lgr5-expressing cells, pointing to a hierarchy of stem cells in the intestinal epithelium. Our results demonstrate that Lgr5-expressing cells are dispensable for normal intestinal homeostasis, and that in the absence of these cells, Bmi1-expressing cells can serve as an alternative stem cell pool. These data provide the first experimental evidence for the interrelationship between these populations. The Bmi1-expressing stem cells may represent both a reserve stem cell pool in case of injury to the small intestine epithelium and a source for replenishment of the Lgr5-expressing cells under non-pathological conditions.

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Shiro Yui, Tetsuya Nakamura, Toshiro Sato … (2012)

Adult stem-cell therapy holds promise for the treatment of gastrointestinal diseases. Here we describe methods for long-term expansion of colonic stem cells positive for leucine-rich repeat containing G protein-coupled receptor 5 (Lgr5(+) cells) in culture. To test the transplantability of these cells, we reintroduced cultured GFP(+) colon organoids into superficially damaged mouse colon. The transplanted donor cells readily integrated into the mouse colon, covering the area that lacked epithelium as a result of the introduced damage in recipient mice. At 4 weeks after transplantation, the donor-derived cells constituted a single-layered epithelium, which formed self-renewing crypts that were functionally and histologically normal. Moreover, we observed long-term (>6 months) engraftment with transplantation of organoids derived from a single Lgr5(+) colon stem cell after extensive in vitro expansion. These data show the feasibility of colon stem-cell therapy based on the in vitro expansion of a single adult colonic stem cell.

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Claudia Andreini, Ivano Bertini, Gabriele Cavallaro … (2008)

We analysed the roles and distribution of metal ions in enzymatic catalysis using available public databases and our new resource Metal-MACiE (http://www.ebi.ac.uk/thornton-srv/databases/Metal_MACiE/home.html). In Metal-MACiE, a database of metal-based reaction mechanisms, 116 entries covering 21% of the metal-dependent enzymes and 70% of the types of enzyme-catalysed chemical transformations are annotated according to metal function. We used Metal-MACiE to assess the functions performed by metals in biological catalysis and the relative frequencies of different metals in different roles, which can be related to their individual chemical properties and availability in the environment. The overall picture emerging from the overview of Metal-MACiE is that redox-inert metal ions are used in enzymes to stabilize negative charges and to activate substrates by virtue of their Lewis acid properties, whereas redox-active metal ions can be used both as Lewis acids and as redox centres. Magnesium and zinc are by far the most common ions of the first type, while calcium is relatively less used. Magnesium, however, is most often bound to phosphate groups of substrates and interacts with the enzyme only transiently, whereas the other metals are stably bound to the enzyme. The most common metal of the second type is iron, which is prevalent in the catalysis of redox reactions, followed by manganese, cobalt, molybdenum, copper and nickel. The control of the reactivity of redox-active metal ions may involve their association with organic cofactors to form stable units. This occurs sometimes for iron and nickel, and quite often for cobalt and molybdenum.

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Author and article information

Contributors

Michal Hershfinkel: Role: Editor

Journal

Journal ID (nlm-ta): PLoS Genet

Journal ID (iso-abbrev): PLoS Genet

Journal ID (publisher-id): plos

Journal ID (pmc): plosgen

Title: PLoS Genetics

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1553-7390

ISSN (Electronic): 1553-7404

Publication date (Electronic): 13 October 2016

Publication date Collection: October 2016

Volume: 12

Issue: 10

Electronic Location Identifier: e1006349

Affiliations

[1 ]RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan

[2 ]Department of Molecular and Medical Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan

[3 ]Laboratory of Histology and Cytology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan

[4 ]Division of Biochemistry, Faculty of Pharmacy, Keio University, Minato-ku, Tokyo, Japan

[5 ]Division of Mucosal Barriology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan

[6 ]Division of Pathology, Department of Oral Diagnostic Sciences, School of Dentistry, Showa University, Shinagawa-ku, Tokyo, Japan

[7 ]Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan

[8 ]Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan

[9 ]Nagahama Institute of Bio-Science and Technology, Tamura, Nagahama, Shiga, Japan

[10 ]Molecular and Cellular Physiology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro, Tokushima, Japan

[11 ]Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Chiba, Japan

[12 ]Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan

[13 ]Department of Gastroenterology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan

[14 ]Equipe de Morphogenese et Signalisation cellulaires UMR 144 CNRS/Institut Curie, Paris, France

[15 ]Division of Stem Cell Cellomics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan

[16 ]Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan

Faculty of Health Sciences, Ben-Gurion University of the Negev, ISRAEL

Author notes

The authors have declared that no competing interests exist.

Conceptualization: WO KH TF.
Data curation: WO KH TF.
Formal analysis: WO KH TF.
Funding acquisition: WO HM KH TF.
Investigation: WO SK TIw YF TIr HI TW AH TH HM.
Methodology: WO KH TF.
Project administration: KH TF.
Resources: OO HK TS SR YH HW KM HO KH TF.
Supervision: TS HO OO HK KH TF.
Validation: WO SK TIw YF KH TF.
Visualization: WO KH TF.
Writing – original draft: WO KH TF.
Writing – review & editing: WO KH TF.

* E-mail: hase-kj@ 123456pha.keio.ac.jp (KH); fukada@ 123456ph.bunri-u.ac.jp (TF)

Author information

Atsushi Hijikata http://orcid.org/0000-0003-4297-8368

Hiroshi Watarai http://orcid.org/0000-0002-7497-4188

Article

Publisher ID: PGENETICS-D-16-00362

DOI: 10.1371/journal.pgen.1006349

PMC ID: 5065117

PubMed ID: 27736879

SO-VID: a80ec309-9593-4af6-b7b2-69d0496f1465

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 14 February 2016

Date accepted : 8 September 2016