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Targeting Senescent Alveolar Epithelial Cells Using Engineered Mesenchymal Stem Cell-Derived Extracellular Vesicles To Treat Pulmonary Fibrosis.

Authors :
Long Y
Yang B
Lei Q
Gao F
Chen L
Chen W
Chen S
Ren W
Cao Y
Xu L
Wu D
Qu J
Li H
Yu Y
Zhang A
Wang S
Chen W
Wang H
Chen T
Chen Z
Li Q
Source :
ACS nano [ACS Nano] 2024 Mar 05; Vol. 18 (9), pp. 7046-7063. Date of Electronic Publication: 2024 Feb 21.
Publication Year :
2024

Abstract

Type 2 alveolar epithelial cell (AEC2) senescence is crucial to the pathogenesis of pulmonary fibrosis (PF). The nicotinamide adenine dinucleotide (NAD <superscript>+</superscript> )-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 <superscript>+</superscript> 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.

Details

Language :
English
ISSN :
1936-086X
Volume :
18
Issue :
9
Database :
MEDLINE
Journal :
ACS nano
Publication Type :
Academic Journal
Accession number :
38381372
Full Text :
https://doi.org/10.1021/acsnano.3c10547