Exosomes Derived from Bone Marrow Mesenchymal Stem Cells attenuate cytokine storm and ARDS in COVID-19 patients.
Exosomes Derived from Bone Marrow Mesenchymal Stem Cells attenuate cytokine storm and ARDS in COVID-19 patients.
Reza Khedri,1,*Anahita Hashempoor,2Mohammad-Reza Mahmoodian-Sani,3Mehrdad Dargahi-Malamir,4Mahsa Fadaei,5
1. Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 2. Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 3. Thalassemia and Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran. 4. Department of Internal Medicine, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran 5. Emergency Department, Imam Khomeini Hospital, Ahvaz Jundishapur Univversity of Medical Sciences, Ahvaz, Iran
Introduction: COVID19 pandemic is still one of the most important concerns of health care systems around the world due to the occurrence of life-threatening pneumonia.
In severe cases, COVID-19 disease is associated with excessive immune response called cytokine storm. Cytokine storm is a potentially fatal condition associated with excessive activation of immune cells and production of inflammatory cytokines and chemical mediators. The cytokine storm induced by COVID-19 is associated with the severity of COVID-19 and progression to ARDS.
ARDS is associated with acute and diffuse inflammatory damage of the alveolar-capillary barrier and increased vascular permeability and decreased lung compliance, leading to pulmonary fibrosis and hypoxemia.
Inflammasomes are one of the most important components of innate immune response that strongly promote inflammation. Inflammasomes play a key role in the pathogenesis of many inflammatory diseases. inflammasome Activation is probably the cause of severe cytokine storm, leading to ARDS and multi organ failure.
current treatments of ARDS including the use of an interleukin-6 antagonist drug called Toslizumab associates with side effects including sepsis, opportunistic infections such as mucormycosis, severe neutropenia, elevated liver enzymes, and coagulation disorders.
Due to the limited effective treatment options and the significant side effects of current treatments for ARDS patients, more effective treatment strategies are needed to suppress the cytokine storm and restore fibrotic lung tissue.
Bone marrow-derived mesenchymal stem cell exosomes (MSC-E) are a complex combination of signaling nano-vesicles exosomes and are novel, multi-targeted, next-generation biologic agents that contain chemokines, growth factors, mRNA, and microRNA with anti-inflammatory, regenerative, and immunomodulatory functions and could be the key to suppress the cytokine storm and improve antiviral defenses in COVID-19.
In this study, we aim to investigate the role of MSC-Es in suppressing cytokine storm and preventing the progression of ARDS in COVID-19 patients.
Methods: Our search was performed in PubMed, SCOPUS, Science direct, EBSCO, ProQuest for published literature until September, 2022 by keywords including COVID-19, exosome, cytokine release syndrome and acute respiratory distress syndrome. The extracted papers were studied and based on defined inclusion criteria, 12 articles from all obtained studies were selected in the current study.
Results: Several preclinical studies show favorable therapeutic effects of MSC-E administered intravenously in animal models of acute lung injury (ALI), ARDS, asthma, and other inflammatory diseases. The analysis of clinical findings indicates a decrease in alveolar inflammation, increase in lung edema clearance, repair of epithelial membranes, and decrease in other consequences of cytokine storm.
Recently, several studies have focused on animal models of ARDS and ALI induced by LPS to understand the mechanism of action of MSC-derived exosomes in reversing fibrosis, ARDS, and acute lung injury.
A study has shown that MSC-Es can reverse ALI through downregulation of nuclear erythroid factor 2 (NrF-2) and antioxidant response element (ARE), leading to ALI treatment. In another study, a positive association between the activation of the NF-κB pathway and the stimulation of the nuclear factor Kappa-B kinase subunit Beta (IKKβ) was reported. This study showed that MSC-E decreases IKKβ and its ubiquitination, thus inhibiting NF-κB and Hedgehog pathways, that both play a key role in epithelial-mesenchymal transition process and lung fibrosis. Also, treatment with MSC-E showed a significant decrease in IFNγ, TNFα, IL-6, and the oxygen saturation level improved significantly after 72 hours of treatment.
few clinical studies have reported the safety and efficacy of exosomes derived from allogeneic bone marrow mesenchymal stem cells in the treatment of severe cases of COVID-19. Improvement of clinical status and the absolute number of neutrophils and lymphopenia with an increase in the mean number of CD3+, CD4+ and CD8+ lymphocytes were reported.
Conclusion: The results show that stem cell-derived exosomes are a promising therapeutic candidate for severe COVID-19 due to their immunogenicity, capacity to restore oxygen, reduce cytokine storm, restore immunity and repairing lung tissue in patients with lung fibrosis and are promising candidates for the treatment of severe cases of COVID-19.