Dual-ligand engineered exosome regulates WNT signaling activation to promote liver repair and regeneration.

Lingyan Yang, Shixiang Wang, Zhiping Qiao, Yue Liu, Xu Wang, Liying Liu, Chunfang Yang, Jiying Ding, Miao Lei, Jiayi Zheng, Wenxiang Hu, Ye-Guang Chen, Yun-Shen Chan

Guangzhou National Laboratory, No.9 Xing Dao Huan Bei Road, Guangzhou International Bio Island, Guangzhou, Guangdong Province, China. · pubmed

Paper

Abstract

WNT signaling is an essential pathway regulating tissue morphogenesis and regeneration. However, harnessing the pathway for regenerative medicine has been challenging due to the lack of approaches to identify and deliver specific WNT ligands to the target tissue. Herein, we reported that WNT and R-spondin (RSPO) proteins could be transported on engineered exosomes and activate the pathway synergistically. We showed that WNT3A and RSPO1 co-treatment could effectively regulate hepatic cell fate and uncovered functional crosstalk with the PPARα signaling pathway. Moreover, dual-ligand-carrying exosome (exoWNT3A/RSPO1) hyperactivated the WNT signaling and promoted efficient hepatic organoid growth compared to the small molecule inhibitor CHIR99021. Importantly, the exosome can be efficiently delivered for robust WNT signaling activation in the liver. Remarkably, exoWNT3A/RSPO1 could accelerate liver repair and regeneration under various conditions, including acute and chronic injuries and aging-associated phenotypes. Collectively, our work revealed the broad therapeutic effects of WNT signaling activation in the liver through the dual-ligand-carrying exosomes.

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Research summary

The paper claims that dual-ligand engineered exosomes can synergistically activate WNT signaling to promote liver repair and regeneration. This research is relevant as it explores mechanisms that could potentially address liver aging and regeneration, which are critical aspects of longevity and age-related decline in organ function.

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