Targeting Senescent Alveolar Epithelial Cells Using Engineered Mesenchymal Stem Cell-Derived Extracellular Vesicles To Treat Pulmonary Fibrosis.
Yaoying LongBianlei YangQian LeiFei GaoLi ChenWenlan ChenSiyi ChenWenxiang RenYulin CaoLiuyue XuDi WuJiao QuHe LiYali YuAnyuan ZhangShan WangWeiqun ChenHongxiang WangTing ChenZhichao ChenQiubai LiPublished in: ACS nano (2024)
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.
Keyphrases
- mesenchymal stem cells
- nk cells
- induced apoptosis
- pulmonary fibrosis
- umbilical cord
- stem cells
- cancer therapy
- risk assessment
- type diabetes
- drug delivery
- bone marrow
- poor prognosis
- signaling pathway
- long non coding rna
- escherichia coli
- adipose tissue
- cell death
- endothelial cells
- current status
- human health
- circulating tumor cells
- smoking cessation
- circulating tumor