上海科技大学知识管理系统

Wnt/b-catenin signaling is an attractive target for regenerative medicine. A powerful driver of stem cell activity and hence tis- sue regeneration, Wnt signaling can promote fibroblast prolif- eration 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/b-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/b-catenin signaling. Inter- estingly, CasRx-mediated Wnt activation specifically in lung epithelium not only promotes alveolar type II cell proliferation and alveolar regeneration but also inhibits lung fibrosis re- sulted from bleomycin-induced injury, relevant in both preven- tive and therapeutic settings. Our study offers an attractive strategy for treating pulmonary fibrosis, with general implica- tions for regenerative medicine.