Mesenchymal stem cell-derived exosomes for treatment of sepsis

Abstract

IntroductionThe pathogenesis of sepsis is an imbalance between pro-inflammatory and anti-inflammatory responses. At the onset of sepsis, the lungs are severely affected, and the injury progresses to acute respiratory distress syndrome (ARDS), with a mortality rate of up to 40%. Currently, there is no effective treatment for sepsis. Cellular therapies using mesenchymal stem cells (MSCs) have been initiated in clinical trials for both ARDS and sepsis based on a wealth of pre-clinical data. However, there remains concern that MSCs may pose a tumor risk when administered to patients. Recent pre-clinical studies have demonstrated the beneficial effects of MSC-derived extracellular vesicles (EVs) for the treatment of acute lung injury (ALI) and sepsis.MethodsAfter recovery of initial surgical preparation, pneumonia/sepsis was induced in 14 adult female sheep by the instillation of Pseudomonas aeruginosa (~1.0×1011 CFU) into the lungs by bronchoscope under anesthesia and analgesia. After the injury, sheep were mechanically ventilated and continuously monitored for 24 h in a conscious state in an ICU setting. After the injury, sheep were randomly allocated into two groups: Control, septic sheep treated with vehicle, n=7; and Treatment, septic sheep treated with MSC-EVs, n=7. MSC-EVs infusions (4ml) were given intravenously one hour after the injury.ResultsThe infusion of MSCs-EVs was well tolerated without adverse events. PaO2/FiO2 ratio in the treatment group tended to be higher than the control from 6 to 21 h after the lung injury, with no significant differences between the groups. No significant differences were found between the two groups in other pulmonary functions. Although vasopressor requirement in the treatment group tended to be lower than in the control, the net fluid balance was similarly increased in both groups as the severity of sepsis progressed. The variables reflecting microvascular hyperpermeability were comparable in both groups.ConclusionWe have previously demonstrated the beneficial effects of bone marrow-derived MSCs (10×106 cells/kg) in the same model of sepsis. However, despite some improvement in pulmonary gas exchange, the present study demonstrated that EVs isolated from the same amount of bone marrow-derived MSCs failed to attenuate the severity of multiorgan dysfunctions.

Unveiling the Role of Exosomes in the Pathophysiology of Sepsis: Insights into Organ Dysfunction and Potential Biomarkers

“…These exosomes transport RNAs and proteins to target cells, demonstrating potential therapeutic effectiveness in preventing sepsis-related complications [134]. MSC exosomes have a safer profile compared to their parent cells, can be stored without losing their function, and possess other advantageous characteristics [135].…”

“…Exosomes have diverse application prospects in sepsis, such as early diagnosis, dynamic disease monitoring, targeted therapy, and potential utilization as a vaccine platform for sepsis prevention [135,136]. However, to fully characterize their biological functions and establish their viability as a treatment option in clinical settings [137], it is crucial to further develop and optimize methods for exosome isolation.…”

The Immunomodulatory Role of Cell-Free Approaches in SARS-CoV-2-Induced Cytokine Storm—A Powerful Therapeutic Tool for COVID-19 Patients

“…Due to their unique ability to interact with recipient cells, the use of exosomes is preferable over the use of CM, and in recent years, they have been increasingly applied in the treatment of several diseases [ 60 ]. For instance, therapy using exosomes resulted in positive outcomes in numerous conditions such as respiratory disorders [ 111 , 112 ], urinary tract infections [ 113 ], intestinal infections [ 114 , 115 ], wound infections [ 116 , 117 , 118 ], neurodegenerative diseases [ 118 , 119 , 120 , 121 ], liver diseases [ 122 , 123 , 124 ], cardiovascular diseases [ 125 , 126 , 127 ], and sepsis [ 128 , 129 ].…”

Advancements in engineered mesenchymal stem cell exosomes for chronic lung disease treatment

“…While the biological characteristics of MSCs confer unique advantages, they also present potential drawbacks. During treatments involving MSCs, the potential risk of tumorigenesis and promoting tumour metastasis should be considered [ 7 , 8 ]. Furthermore, MSCs carry the risk of activating diffuse intravascular coagulation and may increase the risk of thrombosis through the expression of TF/CD142.…”