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Cell Rep. 2017 Mar 14;18(11):2608-2621. doi: 10.1016/j.celrep.2017.02.056.

Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells.

Author information

1
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
2
Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
3
Divisions of Pathology and Laboratory Medicine and Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center and Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
4
Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
5
Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH 45229, USA.
6
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA; Institute for Molecular Medicine, Stem Cells, and Aging and Aging Research Center, Ulm University, 89081 Ulm, Germany. Electronic address: hartmut.geiger@cchmc.org.

Abstract

Although intestinal homeostasis is maintained by intestinal stem cells (ISCs), regeneration is impaired upon aging. Here, we first uncover changes in intestinal architecture, cell number, and cell composition upon aging. Second, we identify a decline in the regenerative capacity of ISCs upon aging because of a decline in canonical Wnt signaling in ISCs. Changes in expression of Wnts are found in stem cells themselves and in their niche, including Paneth cells and mesenchyme. Third, reactivating canonical Wnt signaling enhances the function of both murine and human ISCs and, thus, ameliorates aging-associated phenotypes of ISCs in an organoid assay. Our data demonstrate a role for impaired Wnt signaling in physiological aging of ISCs and further identify potential therapeutic avenues to improve ISC regenerative potential upon aging.

KEYWORDS:

Wnt signaling; aging; intestinal stem cells; regeneration

PMID:
28297666
PMCID:
PMC5987258
DOI:
10.1016/j.celrep.2017.02.056
[Indexed for MEDLINE]
Free PMC Article

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