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Journal Article Ppublish 3 citations

PubMed: 39245939 DOI: 10.1016/j.ymthe.2024.09.008

CasRx-based Wnt activation promotes alveolar regeneration while ameliorating pulmonary fibrosis in a mouse model of lung injury.

Mol Ther 32(11):3974-3989

Authors: Shengxi Shen, Ping Wang, Pei Wu, Pengyu Huang, Tian Chi, Wenqing Xu, Ying Xi

Affiliations

  • School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China.
  • State Key Laboratory of Advanced Medical Materials and Devices, Engineering Research Center of Pulmonary and Critical Care Medicine Technology and Device (Ministry of Education), Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China.
  • School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Department of Immunobiology, Yale University Medical School, New Haven, CT 06520, USA.
  • School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China.

Abstract

Wnt/β-catenin signaling is an attractive target for regenerative medicine. A powerful driver of stem cell activity and hence tissue regeneration, Wnt signaling can promote fibroblast proliferation and activation, leading to fibrosis, while prolonged Wnt signaling is potentially carcinogenic. Thus, to harness its therapeutic potential, the activation of Wnt signaling must be transient, reversible, and tissue specific. In the lung, Wnt signaling is essential for alveolar stem cell activity and alveolar regeneration, which is impaired in lung fibrosis. Activation of Wnt/β-catenin signaling in lung epithelium may have anti-fibrotic effects. Here, we used intratracheal adeno-associated virus 6 injection to selectively deliver CasRx into the lung epithelium, where it reversibly activates Wnt signaling by simultaneously degrading mRNAs encoding Axin1 and Axin2, negative regulators of Wnt/β-catenin signaling. Interestingly, CasRx-mediated Wnt activation specifically in lung epithelium not only promotes alveolar type II cell proliferation and alveolar regeneration but also inhibits lung fibrosis resulted from bleomycin-induced injury, relevant in both preventive and therapeutic settings. Our study offers an attractive strategy for treating pulmonary fibrosis, with general implications for regenerative medicine.

MeSH

Cells, Catenins, Lung, Microscopy, Electron, Scanning Transmission, Fibrosis, Regenerative Medicine, Lung Injury, Stem Cells, Pulmonary Fibrosis, Therapeutics, Tissues, Epithelium, Genetic Therapy

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