Phenylacetylglutamine produced from injury lung alveolar epithelial cells promotes the function of BMSCs by regulating NONRATT006276.2/Mapt pathway

Mesenchymal stem cell (MSC)-based therapy regenerates damaged structures of the respiratory system and restores lung function, thus providing a promising therapeutic approach for chronic obstructive pulmonary disease. Understanding the communication between injured alveolar cells and MSCs can improve the efficiency of MSC-based therapies. The present study analyzed the untargeted metabolomics of the supernatant of AEC-II injury induced by cigarette smoke extract and identified 205 differential metabolites. Phenotypic assays indicated that phenylacetylglutamine (PAG) significantly promoted the migration and mitochondrial function of bone marrow MSCs (BMSCs). Whole-transcriptome sequencing (WT-seq) was used to analyze the long noncoding RNA (lncRNA) and mRNA expression profiles of BMSCs treated with PAG. The upregulated lncNRA NONRATT006276.2 (NRT6276.2) and its trans-regulated gene, microtubule-associated protein tau (Mapt), were identified based on the lncRNA-mRNA co-expression network and bioinformatics analysis. The knockdown of NRT6276.2 or Mapt inhibited the positive effects of PAG on BMSCs. Furthermore, Mapt overexpression reversed the phenotype of BMSCs inhibited by silencing NRT6276.2. In conclusion, PAG enhanced the migration and mitochondrial function of BMSCs by regulating the NRT6276.2/Mapt pathway. This study clarified the positive effects of PAG produced by injured lung cells on transplanted MSCs, providing a potential new strategy to enhance the efficiency of MSC-based therapies.