posted on 2024-02-21, 16:10authored byYaoying Long, Bianlei Yang, Qian Lei, Fei Gao, Li Chen, Wenlan Chen, Siyi Chen, Wenxiang Ren, Yulin Cao, Liuyue Xu, Di Wu, Jiao Qu, He Li, Yali Yu, Anyuan Zhang, Shan Wang, Weiqun Chen, Hongxiang Wang, Ting Chen, Zhichao Chen, Qiubai Li
Type 2 alveolar epithelial
cell (AEC2) senescence is crucial to
the pathogenesis of pulmonary fibrosis (PF). The nicotinamide adenine
dinucleotide (NAD+)-consuming enzyme cluster of differentiation
38 (CD38) is a marker of senescent cells and is highly expressed in
AEC2s of patients with PF, thus rendering it a potential treatment
target. Umbilical cord mesenchymal stem cell (MSC)-derived extracellular
vesicles (MSC-EVs) have emerged as a cell-free treatment with clinical
application prospects in antiaging and antifibrosis treatments. Herein,
we constructed CD38 antigen receptor membrane-modified MSC-EVs (CD38-ARM-MSC-EVs)
by transfecting MSCs with a lentivirus loaded with a CD38 antigen
receptor–CD8 transmembrane fragment fusion plasmid to target
AEC2s and alleviate PF. Compared with MSC-EVs, the CD38-ARM-MSC-EVs
engineered in this study showed a higher expression of the CD38 antigen
receptor and antifibrotic miRNAs and targeted senescent AEC2s cells
highly expressing CD38 in vitro and in naturally aged mouse models
after intraperitoneal administration. CD38-ARM-MSC-EVs effectively
restored the NAD+ levels, reversed the epithelial–mesenchymal
transition phenotype, and rejuvenated senescent A549 cells in vitro,
thereby mitigating multiple age-associated phenotypes and alleviating
PF in aged mice. Thus, this study provides a technology to engineer
MSC-EVs and support our CD38-ARM-MSC-EVs to be developed as promising
agents with high clinical potential against PF.