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Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During Aging.
Hayashi, Yujiro; Asuzu, David T; Bardsley, Michael R; Gajdos, Gabriella B; Kvasha, Sergiy M; Linden, David R; Nagy, Rea A; Saravanaperumal, Siva Arumugam; Syed, Sabriya A; Toyomasu, Yoshitaka; Yan, Huihuang; Chini, Eduardo N; Gibbons, Simon J; Kellogg, Todd A; Khazaie, Khashayarsha; Kuro-O, Makoto; Machado Espindola Netto, Jair; Singh, Mahendra Pal; Tidball, James G; Wehling-Henricks, Michelle; Farrugia, Gianrico; Ordog, Tamas.
Afiliação
  • Hayashi Y; 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. Electronic address: hayashi.yujiro@mayo.edu
  • Asuzu DT; 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.
  • Bardsley MR; 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.
  • Gajdos GB; 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.
  • Kvasha SM; 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.
  • Linden DR; Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
  • Nagy RA; 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.
  • Saravanaperumal SA; 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.
  • Syed SA; 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.
  • Toyomasu Y; 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.
  • Yan H; Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
  • Chini EN; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center and Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota.
  • Gibbons SJ; Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
  • Kellogg TA; Department of Surgery, Mayo Clinic, Rochester, Minnesota.
  • Khazaie K; Department of Immunology, Mayo Clinic, Rochester, Minnesota.
  • Kuro-O M; 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.
  • Machado Espindola Netto J; Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center and Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota.
  • Singh MP; Department of Immunology, Mayo Clinic, Rochester, Minnesota.
  • Tidball JG; Department of Integrative Biology and Physiology, University of California, Los Angeles, California.
  • Wehling-Henricks M; Department of Integrative Biology and Physiology, University of California, Los Angeles, California.
  • Farrugia G; Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
  • Ordog T; 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 Cl
Cell Mol Gastroenterol Hepatol ; 11(1): 117-145, 2021.
Article em En | MEDLINE | ID: mdl-32771388
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Estômago / Envelhecimento / Senescência Celular / Células Intersticiais de Cajal Limite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Cell Mol Gastroenterol Hepatol Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Estômago / Envelhecimento / Senescência Celular / Células Intersticiais de Cajal Limite: Adult / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Cell Mol Gastroenterol Hepatol Ano de publicação: 2021 Tipo de documento: Article