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Senescent lung-resident mesenchymal stem cells drive pulmonary fibrogenesis through FGF-4/FOXM1 axis.
Liu, Yuxin; Ji, Jie; Zheng, Shudan; Wei, Ai; Li, Dongmei; Shi, Bin; Han, Xiaodong; Chen, Xiang.
Afiliação
  • Liu Y; State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China.
  • Ji J; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
  • Zheng S; State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China.
  • Wei A; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
  • Li D; State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China.
  • Shi B; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
  • Han X; State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China.
  • Chen X; State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China.
Stem Cell Res Ther ; 15(1): 309, 2024 Sep 18.
Article em En | MEDLINE | ID: mdl-39289765
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Senescência Celular / Fator 4 de Crescimento de Fibroblastos / Fibrose Pulmonar Idiopática / Células-Tronco Mesenquimais / Proteína Forkhead Box M1 / Pulmão / Camundongos Endogâmicos C57BL Limite: Animals / Humans / Male Idioma: En Revista: Stem Cell Res Ther Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Reino Unido
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: Senescência Celular / Fator 4 de Crescimento de Fibroblastos / Fibrose Pulmonar Idiopática / Células-Tronco Mesenquimais / Proteína Forkhead Box M1 / Pulmão / Camundongos Endogâmicos C57BL Limite: Animals / Humans / Male Idioma: En Revista: Stem Cell Res Ther Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China País de publicação: Reino Unido