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

作者：Yujiro Hayashi, David T. Asuzu, Michael R. Bardsley, Gabriella B. Gajdos, Sergiy M. Kvasha, David R. Linden, Rea 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, Tamás Ördög · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2020 · DOI：10.1016/j.jcmgh.2020.07.011 · 被引用次数：17 · 研究领域：Parathyroid Disorders and Treatments、Gastrointestinal motility and disorders、Magnesium in Health and Disease

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 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: /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.