Mesenchymal stem cell derived proteome can target multiple signalling pathways to ameliorate rheumatoid arthritis: network pharmacology and molecular docking based approach

Abstract

Rheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease with a global prevalence of approximately 1%. Mesenchymal stem cells (MSCs) have been thoroughly investigated for the treatment of RA; however, their clinical use is limited due to issues related to cell engraftment. It is now well established that MSCs exert their regenerative effect through the paracrine mechanism of their secreted factors (called the secretome); however, the mechanism by which secretome proteins target diseases is still unclear. This study aimed to investigate the potential of the proteome of the MSC secretome in targeting the key molecular signatures of RA. Secretome from primary human bone marrow MSCs was collected, and proteomic analysis was performed using label-free tandem mass spectrometry. A network pharmacology approach was used to identify the target genes of the MSC proteome as well as therapeutic targets of RA. Proteomic analysis of the MSC secretome confirmed the presence of 187 unique proteins, with 136 direct human gene targets. 52 of the identified genes were common with the 1922 identified targets of RA. Functional annotations of the 52 genes revealed their involvement in multiple RA-related KEGG pathways, such as ECM-receptor interaction, focal adhesion, the PI3K-AKT SIGNALLING pathway, the phagosome, and the p53 pathway. Molecular docking of the top 10 hub proteins with the PI3K-AKT pathway revealed a strong binding affinity forall the hub proteins, indicating the potential mechanism by which the MSC proteome can be used as a therapeutic cocktail to ameliorate RA.