Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells
Kodandaramireddy Nalapareddy,
Kalpana J. Nattamai,
Rupali S. Kumar,
Rebekah Karns,
Kathryn A. Wikenheiser-Brokamp,
Leesa L. Sampson,
Maxime M. Mahe,
Nambirajan Sundaram,
Mary-Beth Yacyshyn,
Bruce Yacyshyn,
Michael A. Helmrath,
Yi Zheng,
Hartmut Geiger
Affiliations
Kodandaramireddy Nalapareddy
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Kalpana J. Nattamai
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Rupali S. Kumar
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Rebekah Karns
Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Kathryn A. Wikenheiser-Brokamp
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
Leesa L. Sampson
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Maxime M. Mahe
Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Nambirajan Sundaram
Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Mary-Beth Yacyshyn
Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH 45229, USA
Bruce Yacyshyn
Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH 45229, USA
Michael A. Helmrath
Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Yi Zheng
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
Hartmut Geiger
Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA
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.
