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
BACKGROUND: COVID-19 (coronavirus disease 2019) has become a global public health emergency since patients were first detected in Wuhan, China, in December 2019. Currently, there are no satisfying antiviral medications and vaccines available. CASE PRESENTATION: We reported the treatment process and clinical outcome of a 48-year-old man critically ill COVID-19 patient who received transfusion of allogenic human umbilical cord mesenchymal stem cells (UC-MSCs). CONCLUSIONS: We proposed that UC-MSC transfusion might be a new option for critically ill COVID-19. Although only one case we were shown, more similar clinical cases are inquired for further evidence providing the potential effectiveness of UC-MSC treatment.