The short-term and long-term effects of intranasal mesenchymal stem cell administration to noninflamed mice lung

Abstract

Mesenchymal stem cells (mesenchymal stromal cells; MSC)-based therapies remain a promising approach to treat degenerative and inflammatory diseases. Their beneficial effects were confirmed in numerous experimental models and clinical trials. However, safety issues concerning MSCs' stability and their longterm effects limit their implementation in clinical practice, including treatment of respiratory diseases such as asthma, chronic obstructive pulmonary disease, and COVID-19. Here, we aimed to investigate the safety of intranasal application of human adipose tissue-derived MSCs in a preclinical experimental mice model and elucidate their effects on the lungs. We assessed short-term (two days) and long-term (nine days) effects of MSCs administration on lung morphology, immune responses, epithelial barrier function, and transcriptomic profiles. We observed an increased frequency of IFNg-producing T cells and a decrease in occludin and claudin 3 as a long-term effect of MSCs administration. We also found changes in the lung transcriptomic profiles, reflecting redox imbalance and hypoxia signaling pathway. Additionally, we found dysregulation in genes clustered in pattern recognition receptors, macrophage activation, oxidative stress, andFrontiers in Immunology frontiersin.org 01

Mesenchymal Stem/Stromal Cells in Asthma Therapy: Mechanisms and Strategies for Enhancement

“…Recent studies have revealed that delivering human AT-MSCs intranasally to non-inflamed mouse lungs resulted in a low-grade lung inflammation with increased IFN-γ expression, weakened epithelial barrier integrity due to decreased tight junction proteins, activation of innate and adaptive immune responses with elevated IL-7 and T/B cell signaling pathways, and induced redox imbalance characterized by increased HIF1a signaling and superoxide radical degradation. These effects could be attributed to the activation of the recipient organ’s hypoxia pathways in vivo by the transplanted MSCs, which resulted in MSC apoptosis and then triggered a series of graft clearance reactions 132 . Third, the uncontrollable differentiation of MSCs during transplantation has become a safety hazard associated with its application.…”