Mesenchymal Stromal/Stem Cells and Their Products as a Therapeutic Tool to Advance Lung Transplantation

Abstract

Lung transplantation (LTx) has become the gold standard treatment for end-stage respiratory failure. Recently, extended lung donor criteria have been applied to decrease the mortality rate of patients on the waiting list. Moreover, ex vivo lung perfusion (EVLP) has been used to improve the number/quality of previously unacceptable lungs. Despite the above-mentioned progress, the morbidity/mortality of LTx remains high compared to other solid organ transplants. Lungs are particularly susceptible to ischemia-reperfusion injury, which can lead to graft dysfunction. Therefore, the success of LTx is related to the quality/function of the graft, and EVLP represents an opportunity to protect/regenerate the lungs before transplantation. Increasing evidence supports the use of mesenchymal stromal/stem cells (MSCs) as a therapeutic strategy to improve EVLP. The therapeutic properties of MSC are partially mediated by secreted factors. Hence, the strategy of lung perfusion with MSCs and/or their products pave the way for a new innovative approach that further increases the potential for the use of EVLP. This article provides an overview of experimental, preclinical and clinical studies supporting the application of MSCs to improve EVLP, the ultimate goal being efficient organ reconditioning in order to expand the donor lung pool and to improve transplant outcomes.

Stem cell- derived extracellular vesicles as new tools in regenerative medicine - Immunomodulatory role and future perspectives

“…Additionally, in the murine model of lung ischemia-reperfusion injury, administration EVs derived from MSCs attenuated inflammation and edema ( 201 ). Similar outcome was also reported in the rat model, indicating an influence of EVs on the expression of genes regulating inflammation and oxidative stress ( 215 ).…”

Novel approaches for long-term lung transplant survival

“…In the presence of inflammation as occurs in the setting of transplantation, MSCs may be primed to possess an even greater capacity for immunosuppression via TNF-TNFR2 dependent signaling ( 114 , 117 ). MSCs secrete a variety of cytokines, chemokines, and inflammatory factors that regulate the immune system and have anti-oxidative and anti-apoptotic functions ( 118 – 122 ) (reviewed in ( 123 , 124 )). Fourth, because of their large size after in vitro culture, MSCs may become trapped in the lungs following intravenous infusion ( 125 ).…”

“…MSCs, MSC-derived EVs, and MSC-derived conditioned media (which contain EVs) have been evaluated in dozens of studies of lung IRI. Most studies used rodent models with IRI induced by hyperoxia, ventilator damage, E. coli bacteria/LPS, or chemicals such as bleomycin [reviewed in ( 123 )]. Consistently, treatment with MSCs has been found to result in increased survival and decreased lung injury and edema.…”

Current Perspectives on Adult Mesenchymal Stromal Cell-Derived Extracellular Vesicles: Biological Features and Clinical Indications

“…The role of proper differentiation is also being viewed as less necessary, since recent reports more focus on paracrine signaling. Indeed, MSC-EVs are able to improve the diseased organs in several in vivo models, from myocardial infarction to stroke to kidney injury and others [ 83 , 84 , 85 ]. MSC-EVs can thus constitute a promising cell therapy approach in which a cell-free mixture of vesicles is used.…”