Page 66 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Rogers et al. J Transl Med (2020) 18:203 Page 12 of 19

revealed ground glass opacity and 2 days later she was MSC-infused patients demonstrated a decreased level
admitted to the hospital. She was initially treated with of TNF-α, and concurrent elevation in the concentra-
antiviral therapy (lopinavir/ritonavir), IFN-γ inhalation, tion of IL-10, suggesting an improved cytokine milieu.
oseltamivir, and IV injection of moxif oxacin, Xuebijing, RNA-sequencing showed that infused MSCs were nega-
methylprednisolone and immunoglobulin. Her breathing tive for ACE2 and TMPRSS2, which implied that MSCs
was maintained with a non-invasive mechanical ventila- were free from SARS-CoV-2 infection. Also, the Kyoto
tor. Days later she was diagnosed with critically ill type Encyclopedia of Genes and Genomes (KEGG) analysis
COVID-19 with acute respiratory failure and was trans- suggested that MSCs were involved in antiviral pathways.
ferred to the ICU for ventilator support. Eventually, the T e results of these clinical studies in severely ill COVID-
glucocorticoid and antiviral therapies were withdrawn, 19-infected patients show that in vivo administration of
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and 1 week later, 50 × 10 allogeneic UC-MSCs were MSCs may be a safe and ef ective approach for treating
administered intravenously. No obvious adverse ef ects patients who are in pulmonary distress, including elderly
were noted. T e treatment was repeated 3 and 6 days fol- patients with severe ARDS.
lowing the initial treatment. Two days after the infusion Most recently, two commercial companies made press
of her third dose, she was transferred out of the ICU with releases of preliminary results of MSC therapy of serious
normal vital signs and laboratory values and a negative COVID-19 patients. Pluristem announced 100% survival
throat swab test for COVID-19 antigen. Although this of seven patients with 66% of the patients improving their
study was limited to just one critically ill patient, the pos- respiratory parameters [242]. T ey stated that more stud-
itive outcome supports further investigation. ies were planned as well as additional follow-up. No seri-
Leng and colleagues reported similar improvements ous adverse events were reported. Mesoblast reported
with intravenous administration of UC-MSCs into 83% survival in 12 COVID-19 ventilator-dependent
seven patients with COVID-19 noting improved func- patients with ARDS in comparison to 12% survival in
tional outcomes and facilitation of recovery [9, 241]. T e patients not given MSC therapy [243]. T ese preliminary
patients selected were positive for SARS-CoV-2, with results are encouraging.
one displaying critically severe type, four patients exhib-
ited severe types, and two with milder symptoms of dis-
ease. An additional three patients with severe types were Conclusions
enrolled for placebo control. Prior to MSC infusion, all COVID-19 imposes a great public health and socio-
of the patients displayed high fever, shortness of breath, economic burden, especially in low-income and middle-
low oxygen saturation and pneumonia. When symptoms income countries. T ere is an urgent global need for safe
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worsened, the patients received 1 x10 UC-MSCs/kg bw and ef ective treatments. Healthcare services are rapidly
intravenously and were closely followed for 14 days. Vir- becoming overwhelmed by the rise of infected patients
tually all symptoms subsided within 2-4 days subsequent who have developed serious medical illness.
to MSC infusions with no adverse ef ects. Chest CT It may take months to develop and test a vaccine
imaging demonstrated that pneumonia inf ltration sig- which, even if ef ective, will not completely eradicate
nif cantly subsided. T e majority of patients tested neg- viral infection. Until other therapeutics become available,
ative for the SARS-CoV-2 nucleic acid test at a week or cell-based therapies, which have demonstrated safety in
two after MSC infusion. T ey found that MSC could sig- human clinical trials, warrant further investigation. We
nif cantly improve the functional outcomes of 7 patients must act now and utilize a scientif cally rational approach
without any observed adverse ef ects. Although no short- to care for the rapidly growing number of these patients.
term adverse ef ects were observed, long-term follow First with safety studies, and eventually with larger pla-
up after MSC administration will be necessary in future cebo-controlled, randomized clinical trials. Now is the
clinical studies. time for the scientif c community to start such studies, so
T e mechanisms underlying the improvement after we may of er our patients a viable alternative to standard
MSC infusion appears to be the result of robust anti- care.
inf ammatory activity. Such processes include an
increased number of peripheral lymphocytes, the decline Acknowledgements
We thank Sue Harman and Manely Yafeh for editing and formatting support.
in the C-reactive protein, and decrease of over-activated
cytokine-secreting immune cells (CXCR3+ CD4+ T Author’s contributions
cells, CXCR3+ CD8+ T cells, and CXCR3+ NK cells). CR: design, collection and assembly of data, data analysis and interpretation
and manuscript writing and f nal approval. RH: data analysis, preclinical data
Moreover, a group of CD14+ CD11c+ CD11bmid reg- interpretation, and interpretation of manuscript writing. BB: data analysis,
ulatory dendritic cell (DC) population increased after interpretation of manuscript and writing. MS: data analysis, interpretation of
MSC treatment. In comparison to the placebo group, the manuscript and writing. CX: collection of data, data analysis, interpretation of
manuscript. FW: collection of data, data analysis, interpretation of manuscript.