2. Academic Validation
  3. TIGAR/AP-1 axis accelerates the division of Lgr5- reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation

TIGAR/AP-1 axis accelerates the division of Lgr5- reserve intestinal stem cells to reestablish intestinal architecture after lethal radiation

  • Cell Death Dis. 2020 Jul 6;11(7):501. doi: 10.1038/s41419-020-2715-6.
Fei Chen  # 1 2,  Yushuo Zhang  # 2,  Songling Hu 1,  Xiaolin Shi 2,  Zhongmin Wang 3 4,  Zicheng Deng 2,  Longxin Lin 2,  Jianghong Zhang 1,  Yan Pan 1,  Yang Bai 1,  Fenju Liu 2,  Haowen Zhang 5 6,  Chunlin Shao 7
Affiliations

Affiliations

  • 1 Institute of Radiation Medicine, Fudan University, Shanghai, 200032, China.
  • 2 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Suzhou, 215123, China.
  • 3 Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
  • 4 Department of Interventional Radiology, The Third Affiliated Hospital of the Medical College of Shihezi University, Xinjiang, 832008, China.
  • 5 Institute of Radiation Medicine, Fudan University, Shanghai, 200032, China. [email protected].
  • 6 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Jiangsu Provincial Key Laboratory of Radiation Medicine and Protection, Suzhou, 215123, China. [email protected].
  • 7 Institute of Radiation Medicine, Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 32632140 DOI: 10.1038/s41419-020-2715-6
Abstract

During radiologic or nuclear accidents, high-dose ionizing radiation (IR) can cause gastrointestinal syndrome (GIS), a deadly disorder that urgently needs effective therapy. Unfortunately, current treatments based on Natural Products and antioxidants have shown very limited effects in alleviating deadly GIS. Reserve intestinal stem cells (ISCs) and secretory progenitor cells are both reported to replenish damaged cells and contribute to crypt regeneration. However, the suppressed β-catenin/c-Myc axis within these slow-cycling cells leads to limited regenerative response to restore intestinal integrity during fatal accidental injury. Current study demonstrates that post-IR overexpression of TIGAR, a critical downstream target of c-Myc in mouse intestine, mounts a hyperplastic response in Bmi1-creERT+ reserve ISCs, and thus rescues mice from lethal IR exposure. Critically, by eliminating damaging Reactive Oxygen Species (ROS) yet retaining the proliferative ROS signals, TIGAR-overexpression enhances the activity of activator protein 1, which is indispensable for initiating reserve-ISC division after lethal radiation. In addition, it is identified that TIGAR-induction exclusively gears the Lgr5- subpopulation of reserve ISCs to regenerate crypts, and intestinal TIGAR-overexpression displays equivalent intestinal reconstruction to reserve-ISC-restricted TIGAR-induction. Our findings imply that precise administrations toward Lgr5- reserve ISCs are promising strategies for unpredictable lethal injury, and TIGAR can be employed as a therapeutic target for unexpected radiation-induced GIS.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12270
    99.59%, c-Fos/AP-1 Inhibitor