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MSC-EVs Modulate Airway Epithelial Cell Function

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that give rise to cells of the skeletal system including cartilage (chondrocytes), bone (osteoblasts), and fat cells (adipocytes). MSCs play an important role in tissue repair, growth, wound healing and as such, they are of great potential in regenerative medicine applications such as bone/cartilage repair, treatment of cardiac, lung disease and more. Researchers have identified MSCs in all tissues of the body but currently, the main sources of MSCs for research and therapeutic applications are from bone marrow (BM-MSCs) and adipose tissue (ADMSCs). The paracrine effects of these cells are largely responsible for their therapeutic efficacy where MSC-secreted extracellular vesicles (EV) play a central role. The transplantation of MSC-EV confers several advantages, such as higher safety profile, lower immunogenicity, and the ability to cross biological barriers, avoiding many of the complications of MSC transplantation such as immune rejection and tumor formation.

Human lung small airway epithelial (AE) cells are involved in the pathophysiology of several lung diseases such as asthma, chronic obstructive pulmonary disease, and bronchogenic carcinoma. In a variety of lung disease models and clinical trials, the transplantation of MSC-EVs was found to exert a positive effect on AE cells in lung tissue. Based on these positive results, Schmelzer and Colleagues designed experiments to pinpoint the in vitro mechanism of action by which MSC-EVs exert their effect on AE cell behavior and to identify any potential differences between EVs derived from BM-MSC and ADMSC tissue sources.

To look at the effect of MSC secretions only, on AE cell behavior, Lifeline’s human bone marrow and adipose-derived MSCs were seeded onto Transwell inserts and cocultured with AE cells. This in vitro system enabled the researchers to prevent cellular contact but still allow the two cell types to share the same culture media. Modulation of AE cell behavior was quantified by cell proliferation, cell viability, gene expression, and changes in secretion and uptake of AE cell-specific growth factors.

In coculture with MSCs, AE cell proliferation rate and viability, assessed by OD565nm in an LDH assay, were elevated compared to controls. Real-time PCR quantified changes in the expression of AE-specific genes where mucin 1 (MUC1) and intercellular adhesion molecule 1 (ICAM1), genes important in regulating the anti-inflammatory response in AE cells, were increased 2- and 4-fold, respectively, in MSC coculture over controls. Interestingly, the only difference in response detected in this study to BM-MSC and ADMSC coculture was in the uptake of angiopoietin-2 by AE cells from the culture medium quantified by ELISA. The uptake of angiopoietin-2 in AE cells dropped to nearly zero only in coculture with ADMSC. In contrast to other angiogenic growth factors, such as angiopoietin-1 and vascular endothelial growth factor, known to stimulate vascular regeneration, the role of angiopoietin-2 is unclear. Some evidence suggests a beneficial effect of inhibition of angiopoietin-2 in cardiac transplantation to prevent transplant ischemia-reperfusion injury and chronic rejection but this differential uptake of angiopoietin-2 caused by AE cells warrants further investigation.

From the data generated here, the authors confirm that MSC-EVs confer a positive effect on AE cells by increasing their proliferative capacity and enhancing their anti-inflammatory responses. Importantly, while the majority of AE effects exerted by MSC-EVs were similar regardless of tissue source, the difference in uptake of angiopoietin 2 will need to be considered depending on the clinical application.

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