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
With the wide application and constantly advancing of traditional Chinese medicine(TCM) in the prevention and control of COVID-19, many innovative achievements have been made in the prevention and treatment of COVID-19 by TCM. Analyzing the patent information of related innovations timely will not only help researcher to use patent information more quickly to mine and screen more effective drugs, but also help inspiring R&D personnel to strengthen patent protection for innovations. This article is based on Chinese Clinical Guidance for COVID-19 Diagnosis and Treatment (6th edition) published by National Health Commitssion of the People's Republic of China, analyses related patent information on recommended Chinese patent medicines in medical observation period, and basic prescriptions, recommended prescriptions and recommended Chinese patent medicines in clinical treatment period, describes the patent technology roadmap of recommended prescriptions and recommended Chinese patent medicines, analyzes key patent information, and tries to provide useful reference for scientific research of TCM.