Potential application of mesenchymal stem cells and their exosomes in lung injury: an emerging therapeutic option for COVID-19 patients

Abstract

The COVID-19 pandemic has negatively impacted the global public health and the international economy; therefore, there is an urgent need for an effective therapy to treat COVID-19 patients. Mesenchymal stem cells (MSCs) have been proposed as an emerging therapeutic option for the SARS-CoV-2 infection. Recently, numerous clinical trials have been registered to examine the safety and efficacy of different types of MSCs and their exosomes for treating COVID-19 patients, with less published data on the mechanism of action. Although there is no approved effective therapy for COVID-19 as of yet, MSC therapies showed an improvement in the treatment of some COVID-19 patients. MSC’s therapeutic effect is displayed in their ability to reduce the cytokine storm, enhance alveolar fluid clearance, and promote epithelial and endothelial recovery; however, the safest and most effective route of MSC delivery remains unclear. The use of poorly characterized MSC products remains one of the most significant drawbacks of MSC-based therapy, which could theoretically promote the risk for thromboembolism. Optimizing the clinical-grade production of MSCs and establishing a consensus on registered clinical trials based on cell-product characterization and mode of delivery would aid in laying the foundation for a safe and effective therapy in COVID-19. In this review, we shed light on the mechanistic view of MSC therapeutic role based on preclinical and clinical studies on acute lung injury and ARDS; therefore, offering a unique correlation and applicability in COVID-19 patients. We further highlight the challenges and opportunities in the use of MSC-based therapy.

MSC-derived exosomes carrying a cocktail of exogenous interfering RNAs an unprecedented therapy in era of COVID-19 outbreak

“…Despite its tremendous benefits, utilizing MSCs as immunomodulatory and regenerative agents is not devoid of limitations, particularly when administered through the IV route [ 25 ]. For example, these cells might be entrapped at the capillary level and can be almost cleared from the circulation, with a small proportion of them surviving on their way to the target site [ 26 , 27 ].…”

“…Therefore, for efficient trafficking of the cells to the target site, a sufficient cell number needs to be administered and monitored, which can be a resource-consuming process [ 28 ]. Moreover, MSCs express tissue factor (TF/CD142) that raises the concern of thromboembolic events [ 25 ].…”

Therapeutic Potential of Mesenchymal Stem Cells and Their Products in Lung Diseases—Intravenous Administration versus Inhalation

“…Another advantage is the ability of storage of EVs in the absence of DMSO, which may have biological effects. Further, the absence of HLA I -and HLA II expression provides them with lower immunogenicity than MSCs, which express HLA I constitutively and HLA II after stimulation with IFN-γ [60]. EVs do not activate the complement system or induce opsonization of antigen-presenting cells like MSCs.…”

“…Another negative aspect of intravenous administration of MSCs is their thrombotic effect through formation of cell aggregates and complement activation [25,62]. Intratracheal delivery may be further useful for patients needing extracorporeal membrane oxygenation (ECMO) because MSCs attach to the membrane oxygenator fibers [60]. This could be prevented by infusing the cells prior to ECMO in patients not needing continuous high-flow ECMO.…”

Mechanistic and Therapeutic Implications of Extracellular Vesicles as a Potential Link Between Covid-19 and Cardiovascular Disease Manifestations

“…Therapeutic approaches for Covid-19 based on MSCs-derived EVs aimed to enhancing the healing process following lung injury, have been taken in consideration ( Akbari and Rezaie, 2020 ; Al-Khawaga and Abdelalim, 2020 ; Pinky et al, 2020 ; Tsuchiya et al, 2020 ). However, experimental evidences of their mechanism of action, and whether MSCs-derived EVs therapy can ameliorate cardiovascular manifestations have not been elucidated.…”