ABSTRACT
The infusion of coronavirus disease 2019 (COVID-19) patients with mesenchymal stem cells (MSCs) potentially improves clinical symptoms, but the underlying mechanism remains unclear. We conducted a randomized, single-blind, placebo-controlled (29 patients/group) phase II clinical trial to validate previous findings and explore the potential mechanisms. Patients treated with umbilical cord-derived MSCs exhibited a shorter hospital stay (P = 0.0198) and less time required for symptoms remission (P = 0.0194) than those who received placebo. Based on chest images, both severe and critical patients treated with MSCs showed improvement by day 7 (P = 0.0099) and day 21 (P = 0.0084). MSC-treated patients had fewer adverse events. MSC infusion reduced the levels of C-reactive protein, proinflammatory cytokines, and neutrophil extracellular traps (NETs) and promoted the maintenance of SARS-CoV-2-specific antibodies. To explore how MSCs modulate the immune system, we employed single-cell RNA sequencing analysis on peripheral blood. Our analysis identified a novel subpopulation of VNN2+ hematopoietic stem/progenitor-like (HSPC-like) cells expressing CSF3R and PTPRE that were mobilized following MSC infusion. Genes encoding chemotaxis factors - CX3CR1 and L-selectin - were upregulated in various immune cells. MSC treatment also regulated B cell subsets and increased the expression of costimulatory CD28 in T cells in vivo and in vitro. In addition, an in vivo mouse study confirmed that MSCs suppressed NET release and reduced venous thrombosis by upregulating kindlin-3 signaling. Together, our results underscore the role of MSCs in improving COVID-19 patient outcomes via maintenance of immune homeostasis.
Subject(s)
COVID-19/therapy , Immunomodulation , Mesenchymal Stem Cell Transplantation , Aged , Animals , Antibodies, Viral/blood , B-Lymphocyte Subsets/cytology , B-Lymphocyte Subsets/immunology , B-Lymphocyte Subsets/metabolism , C-Reactive Protein/analysis , COVID-19/immunology , COVID-19/virology , Cytokines/genetics , Cytokines/metabolism , Cytoskeletal Proteins/metabolism , Disease Models, Animal , Extracellular Traps/metabolism , Female , Humans , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/metabolism , Male , Mice , Mice, Inbred C57BL , Middle Aged , SARS-CoV-2/isolation & purification , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Venous Thrombosis/metabolism , Venous Thrombosis/pathologyABSTRACT
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Subject(s)
COVID-19/metabolism , Inflammation/metabolism , Ischemic Stroke/metabolism , Thrombophilia/metabolism , Aged , Aged, 80 and over , Blood Sedimentation , C-Reactive Protein/metabolism , COVID-19/complications , Cluster Analysis , Female , Ferritins/metabolism , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinogen/metabolism , Hospital Mortality , Humans , Interleukin-6/metabolism , Ischemic Stroke/complications , L-Lactate Dehydrogenase/metabolism , Leukocyte Count , Logistic Models , Machine Learning , Male , Middle Aged , Myocardial Infarction/complications , Myocardial Infarction/metabolism , Partial Thromboplastin Time , Pulmonary Embolism/complications , Pulmonary Embolism/metabolism , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Venous Thrombosis/complications , Venous Thrombosis/metabolismABSTRACT
The novel coronavirus (severe acute respiratory syndrome CoV-2 [SARS-CoV-2]), also known as COVID-19, is a single-stranded enveloped RNA virus that created a Public Health Emergency of International Concern in January 2020, with a global case burden of over 15 million in just 7 months. Infected patients develop a wide range of clinical manifestations-typically presenting with fever, cough, myalgia, and fatigue. Severely ill patients may fall victim to acute respiratory distress syndrome, acute heart injuries, neurological manifestations, or complications due to secondary infections. These critically ill patients are also found to have disrupted coagulation function, predisposing them to consumptive coagulopathies, and both venous and thromboembolic complications. Common laboratory findings include thrombocytopenia, elevated D-dimer, fibrin degradation products, and fibrinogen, all of which have been associated with greater disease severity. Many cases of pulmonary embolism have been noted, along with deep vein thrombosis, ischemic stroke, myocardial infarction, and systemic arterial embolism. The pathogenesis of coronavirus has not been completely elucidated, but the virus is known to cause excessive inflammation, endothelial injury, hypoxia, and disseminated intravascular coagulation, all of which contribute to thrombosis formation. These patients are also faced with prolonged immobilization while staying in the hospital or intensive care unit. It is important to have a high degree of suspicion for thrombotic complications as patients may rapidly deteriorate in severe cases. Evidence suggests that prophylaxis with anticoagulation may lead to a lower risk of mortality, although it does not eliminate the possibility. The risks and benefits of anticoagulation treatment should be considered in each case. Patients should be regularly evaluated for bleeding risks and thrombotic complications.