Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During Aging.,Cellular and Molecular Gastroenterology and Hepatology

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Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During Aging.
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2020-08-07 , DOI: 10.1016/j.jcmgh.2020.07.011
Yujiro Hayashi ₁ , David T Asuzu ₁ , Michael R Bardsley ₁ , Gabriella B Gajdos ₁ , Sergiy M Kvasha ₁ , David R Linden ₂ , Rea A Nagy ₁ , Siva Arumugam Saravanaperumal ₁ , Sabriya A Syed ₁ , Yoshitaka Toyomasu ₁ , Huihuang Yan ₃ , Eduardo N Chini ₄ , Simon J Gibbons ₂ , Todd A Kellogg ₅ , Khashayarsha Khazaie ₆ , Makoto Kuro-O ₇ , Jair Machado Espindola Netto ₄ , Mahendra Pal Singh ₆ , James G Tidball ₈ , Michelle Wehling-Henricks ₈ , Gianrico Farrugia ₂ , Tamas Ordog ₉

Affiliation

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.
Enteric Neuroscience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
Signal Transduction and Molecular Nutrition Laboratory, Kogod Aging Center and Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota.
Department of Surgery, Mayo Clinic, Rochester, Minnesota.
Department of Immunology, Mayo Clinic, Rochester, Minnesota.
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.
Department of Integrative Biology and Physiology, University of California, Los Angeles, California.
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.

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, APC^Δ468 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.

中文翻译：

Wnt 诱导的、TRP53 介导的细胞周期停滞是衰老过程中 Cajal 耗竭的间质细胞的基础。

背景与目标

老年人的胃功能障碍可能导致食物摄入减少、虚弱和死亡率增加。Cajal (ICC) 的起搏器和神经调节细胞间质细胞随着人类年龄的增长而下降，并且它们的损失会导致抗衰老 Klotho 蛋白亚型的早衰klotho小鼠的胃功能障碍。ICC 消耗的机制仍不清楚。Klotho 衰减 Wnt（无翼型 MMTV 集成站点）信号。在这里，我们通过上调 ICC 干细胞 (ICC-SC) 中的转化相关蛋白 TRP53 来检查未对抗的 Wnt 信号是否可以成为衰老相关的 ICC 损失的基础。

方法

老化1-107周的小鼠，Klotho的小鼠中，APC ^Δ468与过度活跃的Wnt信号，鼠标ICC-SC，和人胃平滑肌小鼠通过RNA测序，反转录-聚合酶链反应，免疫印迹，免疫荧光，组织化学研究，流式细胞术，和甲基四唑、乙炔基/溴脱氧尿苷掺入和离体胃顺应性测定。通过药理学和基因过表达和 RNA 干扰对细胞进行了操作。

结果

该klotho基因与老年小鼠表现出类似的ICC损失和损害胃合规性。ICC-SC 下降先于 ICC 耗尽。经典 Wnt 信号和 TRP53 在klotho和老年小鼠以及中年人的胃肌肉中增加。过度刺激的经典 Wnt 信号会增加 DNA 损伤反应和 TRP53，并减少 ICC-SC 自我更新和胃 ICC。TRP53 诱导持续抑制 G ₁ /S 和 G ₂ /M 细胞周期相变而不激活细胞凋亡、自噬、细胞静止或衰老的典型标志物/介质。G ₁ /S 阻滞反映了细胞周期蛋白依赖性激酶抑制剂 1B 的增加和细胞外信号调节激酶活性降低导致的细胞周期蛋白 D1 的减少。