title: Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells.
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.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Kodandaramireddy
authors.initials: K
authors.lastname: Nalapareddy
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Kalpana J
authors.initials: KJ
authors.lastname: Nattamai
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Rupali S
authors.initials: RS
authors.lastname: Kumar
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Karns
authors.affiliation: 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.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Wikenheiser-Brokamp
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Leesa L
authors.initials: LL
authors.lastname: Sampson
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Maxime M
authors.initials: MM
authors.lastname: Mahe
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Nambirajan
authors.initials: N
authors.lastname: Sundaram
authors.affiliation: Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Mary-Beth
authors.initials: MB
authors.lastname: Yacyshyn
authors.affiliation: Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Yacyshyn
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Helmrath
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002452:Cell Count; D049109:Cell Proliferation; D016922:Cellular Senescence; D005260:Female; D007421:Intestine, Small / Q000166:cytology*; D051379:Mice; D009940:Organoids / Q000166:cytology; D012038:Regeneration; D055153:Stem Cell Niche; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D015415:Biomarkers
keywords: Wnt signaling; aging; intestinal stem cells; regeneration