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  3. Senescent lung-resident mesenchymal stem cells drive pulmonary fibrogenesis through FGF-4/FOXM1 axis

Senescent lung-resident mesenchymal stem cells drive pulmonary fibrogenesis through FGF-4/FOXM1 axis

  • Stem Cell Res Ther. 2024 Sep 18;15(1):309. doi: 10.1186/s13287-024-03866-2.
Yuxin Liu # 1 2,  Jie Ji # 1 2,  Shudan Zheng 1 2,  Ai Wei 1,  Dongmei Li 1 2,  Bin Shi 3,  Xiaodong Han 4 5 6,  Xiang Chen 7 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China.
  • 2 Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
  • 3 Pulmonary and Critical Care Medicine, Suqian People's Hospital of Nanjing Gulou Hospital Group, Suqian Scientific Research Institute of Nanjing University Medical School, Nanjing University, Suqian, Jiangsu, 223800, China. shibin01230123@126.com.
  • 4 State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China. hanxd@nju.edu.cn.
  • 5 Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China. hanxd@nju.edu.cn.
  • 6 Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, China. hanxd@nju.edu.cn.
  • 7 State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China. chenxiang910110@163.com.
  • 8 Department of Basic Medical Science, Jiangsu Vocational College of Medicine, Yancheng, Jiangsu, 224008, China. chenxiang910110@163.com.
  • 9 State Key Laboratory of Pharmaceutical Biotechnology, Division of Sports Medicine and Adult Reconstructive Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China. chenxiang910110@163.com.
  • # Contributed equally.
PMID: 39289765 DOI: 10.1186/s13287-024-03866-2
Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is an age-related disease featured with abnormal fibrotic response and compromised lung function. Cellular senescence is now considered as an essential driving mechanism for IPF. Given the poor knowledge of the mechanisms underpinning IPF progression, understanding the cellular processes and molecular pathways is critical for developing effective therapies of IPF.

Methods: Lung fibrosis was induced using bleomycin in C57BL/6 mice. Cellular senescence was measured by immunofluorescence. The effects of FGF-4 on fibroblast activation markers and signaling molecules were assessed with western blot and qPCR.

Results: We demonstrated elevated abundance of senescent mesenchymal stem cells (MSCs) in IPF lung tissues, which was tightly correlated with the severity of pulmonary fibrosis in vivo. In addition, senescent MSCs could effectively induce the phenotype of pulmonary fibrosis both in vitro and in vivo. To further confirm how senescent MSCs regulate IPF progression, we demonstrate that FGF-4 is significantly elevated in senescent MSCs, which can induce the activation of pulmonary fibroblasts. In vitro, FGF-4 can activate Wnt signaling in a FOXM1-dependent manner. Inhibition of FOXM1 via thiostrepton effectively impairs FGF-4-induced activation of pulmonary fibroblast and dramatically suppresses the development of pulmonary fibrosis.

Conclusion: These findings reveal that FGF-4 plays a crucial role in senescent MSCs-mediated pulmonary fibrogenesis, and suggests that strategies aimed at deletion of senescent MSCs or blocking the FGF-4/FOXM1 axis could be effective in the therapy of IPF.

Keywords

Cellular senescence; FGF-4; FOXM1; Idiopathic pulmonary fibrosis; Mesenchymal stem cells.

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