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.

中文翻译：

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基于 CasRx 的 Wnt 激活促进肺泡再生，同时改善肺损伤小鼠模型中的肺纤维化


Wnt/β-catenin 信号转导是再生医学的一个有吸引力的靶点。Wnt 信号转导是干细胞活性和组织再生的强大驱动力，可促进成纤维细胞增殖和活化，导致纤维化，而延长的 Wnt 信号转导可能致癌。因此，为了利用其治疗潜力，Wnt 信号转导的激活必须是瞬时、可逆和组织特异性的。在肺中，Wnt 信号转导对于肺泡干细胞活性和肺泡再生至关重要，这在肺纤维化中会受损。肺上皮中 Wnt/β-catenin 信号转导的激活可能具有抗纤维化作用。在这里，我们使用气管内腺相关病毒 6 注射选择性地将 CasRx 递送到肺上皮细胞中，在那里它通过同时降解编码 Wnt/β-catenin 信号传导的负调节因子 Axin1 和 Axin2 的 mRNA 来可逆地激活 Wnt 信号传导。有趣的是，CasRx 介导的 Wnt 激活特异性地在肺上皮中，不仅促进肺泡 II 型细胞增殖和肺泡再生，还抑制博来霉素诱导损伤引起的肺纤维化，这与预防和治疗环境相关。我们的研究为治疗肺纤维化提供了一种有吸引力的策略，对再生医学具有普遍意义。