Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During AgingSummary

Yujiro Hayashi; David T. Asuzu; Michael R. Bardsley; Gabriella B. Gajdos; Sergiy M. Kvasha; David R. Linden; Rea A. Nagy; Siva Arumugam Saravanaperumal; Sabriya A. Syed; Yoshitaka Toyomasu; Huihuang Yan; Eduardo N. Chini; Simon J. Gibbons; Todd A. Kellogg; Khashayarsha Khazaie; Makoto Kuro-o; Jair Machado Espindola Netto; Mahendra Pal Singh; James G. Tidball; Michelle Wehling-Henricks; Gianrico Farrugia; Tamas Ordog

Cellular and Molecular Gastroenterology and Hepatology (Jan 2021)

Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During AgingSummary

Yujiro Hayashi,
David T. Asuzu,
Michael R. Bardsley,
Gabriella B. Gajdos,
Sergiy M. Kvasha,
David R. Linden,
Rea A. Nagy,
Siva Arumugam Saravanaperumal,
Sabriya A. Syed,
Yoshitaka Toyomasu,
Huihuang Yan,
Eduardo N. Chini,
Simon J. Gibbons,
Todd A. Kellogg,
Khashayarsha Khazaie,
Makoto Kuro-o,
Jair Machado Espindola Netto,
Mahendra Pal Singh,
James G. Tidball,
Michelle Wehling-Henricks,
Gianrico Farrugia,
Tamas Ordog

Affiliations

Yujiro Hayashi: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; Yujiro Hayashi, PhD, Mayo Clinic, Guggenheim 10, 200 First Street SW, Rochester, Minnesota 55906. fax: (507) 255-6318.
David T. Asuzu: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
Michael R. Bardsley: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
Gabriella B. Gajdos: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
Sergiy M. Kvasha: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
David R. Linden: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
Rea A. Nagy: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
Siva Arumugam Saravanaperumal: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
Sabriya A. Syed: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
Yoshitaka Toyomasu: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota
Huihuang Yan: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
Eduardo N. Chini: Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center and Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota
Simon J. Gibbons: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
Todd A. Kellogg: Department of Surgery, Mayo Clinic, Rochester, Minnesota
Khashayarsha Khazaie: Department of Immunology, Mayo Clinic, Rochester, Minnesota
Makoto Kuro-o: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Division of Anti-aging Medicine, Center for Molecular Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan
Jair Machado Espindola Netto: Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center and Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota
Mahendra Pal Singh: Department of Immunology, Mayo Clinic, Rochester, Minnesota
James G. Tidball: Department of Integrative Biology and Physiology, University of California, Los Angeles, California
Michelle Wehling-Henricks: Department of Integrative Biology and Physiology, University of California, Los Angeles, California
Gianrico Farrugia: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
Tamas Ordog: Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, Minnesota; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota; Correspondence Address correspondence to: Tamas Ordog, MD, Mayo Clinic, Guggenheim 10, 200 First Street SW, Rochester, Minnesota 55906. fax: (507) 255-6318.

Journal volume & issue: Vol. 11, no. 1
pp. 117 – 145

Abstract

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Background & Aims: Gastric dysfunction in the elderly may cause reduced food intake, frailty, and increased mortality. The pacemaker and neuromodulator cells interstitial cells of Cajal (ICC) decline with age in humans, and their loss contributes to gastric dysfunction in progeric klotho mice hypomorphic for the anti-aging Klotho protein. The mechanisms of ICC depletion remain unclear. Klotho attenuates Wnt (wingless-type MMTV integration site) signaling. Here, we examined whether unopposed Wnt signaling could underlie aging-associated ICC loss by up-regulating transformation related protein TRP53 in ICC stem cells (ICC-SC). Methods: Mice aged 1–107 weeks, klotho mice, APCΔ468 mice with overactive Wnt signaling, mouse ICC-SC, and human gastric smooth muscles were studied by RNA sequencing, reverse transcription–polymerase chain reaction, immunoblots, immunofluorescence, histochemistry, flow cytometry, and methyltetrazolium, ethynyl/bromodeoxyuridine incorporation, and ex-vivo gastric compliance assays. Cells were manipulated pharmacologically and by gene overexpression and RNA interference. Results: The klotho and aged mice showed similar ICC loss and impaired gastric compliance. ICC-SC decline preceded ICC depletion. Canonical Wnt signaling and TRP53 increased in gastric muscles of klotho and aged mice and middle-aged humans. Overstimulated canonical Wnt signaling increased DNA damage response and TRP53 and reduced ICC-SC self-renewal and gastric ICC. TRP53 induction persistently inhibited G1/S and G2/M cell cycle phase transitions without activating apoptosis, autophagy, cellular quiescence, or canonical markers/mediators of senescence. G1/S block reflected increased cyclin-dependent kinase inhibitor 1B and reduced cyclin D1 from reduced extracellular signal-regulated kinase activity. Conclusions: Increased Wnt signaling causes age-related ICC loss by up-regulating TRP53, which induces persistent ICC-SC cell cycle arrest without up-regulating canonical senescence markers.

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

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