Journal
CELL RESEARCH
Volume 31, Issue 12, Pages 1244-1262Publisher
SPRINGERNATURE
DOI: 10.1038/s41422-021-00573-y
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Categories
Funding
- National Key R&D Program of China [2016YFA0101000, 2016YFA0101001, 2016YFA0101002, 2016YFA0101003, 2018YFA0109800, 2020YFA0113000, 2020YFA0113001]
- National Key R&D Program of China key special project of public security risk prevention and control and emergency technical equipment [2020YFC0844000]
- CAMS Innovation Fund for Medical Sciences [2017-I2M-3-007]
- 111 Project [B18007]
- National Natural Science Foundation of China [81971324, 81672313, 81700782, 81972523, 81771349, 31770967, 31571177, 31972901, 31571430]
- Wuhan Municipal Health scientific research project [EX20E16]
- Beijing Science Foundation of China [Z201100001020004, Z201100005520062, Z201100007920017]
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Treatment of COVID-19 patients with mesenchymal stem cells (MSCs) showed positive outcomes in terms of shorter hospital stays, faster symptom remission, and improved chest images, with reduced adverse events. MSC infusion modulated the immune system by decreasing inflammatory markers, promoting SARS-CoV-2-specific antibodies, and activating specific immune cell populations. Furthermore, MSCs suppressed NET release and reduced venous thrombosis, highlighting their role in improving patient outcomes via immune homeostasis.
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.
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