Page 64 - Mesenchymal Stem cells, Exosomes and vitamins in the fight aginst COVID

Rogers et al. J Transl Med (2020) 18:203 Page 10 of 19

tissue factor is responsible for systemic activation of the ASCs/kg bw or vehicle control. T ere were no infusion
coagulation system, upon intravenous infusion it did not toxicities or serious adverse events and no signif cant dif-
inf uence microvascular thrombus formation in the lungs ferences in the overall number of adverse events between
in a murine bacterial pneumonia model [225]. the two groups. A short-term improvement was observed
Perlee et al. studied the safety and potential use of IV in oxygenation after ASC infusion, but ventilator-free
infused allogeneic ASCs in 32 healthy subjects who had days, ICU-free days, and length of hospital stay were
received IV purif ed lipopolysaccharide (LPS), a well char- unchanged.
acterized model of human inf ammation. Patients were T e results of a phase I, multi-center, open label,
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injected with up to 4 × 10 ASCs/kg bw. Transient increases dose escalation pilot study (STem cells for ARDS Treat-
in plasma thrombin-antithrombin complexes (TATc) and ment; START) were reported by Wilson et al. [55]. Nine
D-dimer were noted. ASC infusion did not modify plasmi- patients with moderate to severe ARDS received a single
nogen-activator inhibitor type I (PAI-1) concentrations and intravenous administration of allogeneic BM-MSCs with
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inhibited the LPS-induced plasma tissue-type plasminogen low dose (1x10 BM-MSCs/kg bw), intermediate dose
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activator (tPA) elevations. Clinically, ASC infusions were (5x10 BM-MSCs/kg bw) or high dose BM-MSCs (10x10
well tolerated. T ere were no serious adverse events and BM-MSCs/kg bw). No evidence of infusion-related clini-
arterial oxygen saturations did not dif er from the placebo cal instability, adverse events or toxicity was observed at
control group. Similar transient procoagulant ef ects have any of the doses tested. High dose BM-MSCs improved
been demonstrated with bone-marrow derived MSCs and daily sequential organ failure assessment (SOFA) score
placental derived decidual stromal cells without causing compared to lower doses. However, no signif cant dif-
thrombotic events [226]. ferences in ARDS markers (IL-6, IL-8, ANGPT2, and
Liao et al. used heparin therapy to increase the safety of AGER) were detected in any of the samples collected.
high dose BM-MSC infusion and successfully prevented Two patients died within 60 days of treatment, but their
the coagulation abnormalities caused by tissue factor death was not attributed to the infusion of BM-MSCs.
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overexpression in vivo [227]. In humans, anticoagulation Simonson et al. tested the IV administration of 2 × 10
protocols have been shown to reduce the risk of throm- cells/kg bw of allogeneic BM-MSCs in two patients with
boembolism in patients with ARDS caused by inf uenza A severe refractory ARDS who had failed to improve after
H1N1 infection [228]. T e clinical relevance of the proco- all supportive therapies. Both patients recovered from
agulant ef ects of MSCs is unknown, however thrombotic multiple organ failure and presented reduced markers of
events following administration of MSCs derived from epithelial apoptosis, alveolar-capillary f uid leakage, pro-
many dif erent tissue sources have not been reported [168]. inf ammatory cytokines, miRNAs, and chemokines in
Concerns regarding coagulopathy with the use of ASCs in BAL f uid and plasma [229, 231].
ARDS and sepsis patients have not been realized in placebo Matthay and colleagues reported the results from a
controlled clinical trials, but these patients typically receive prospective, double-blind multi-center, randomized trial
anticoagulation prophylaxis. Matthay et al. [229] stud- (START study) to assess BM-MSC treatment in ARDS
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ied the safety of IV infusion of allogeneic high dose BM- [229]. A single intravenous dose of 10 × 10 BM-MSCs/
MSCs in 40 patients with moderate to severe ARDS, 61% kg bw was compared with placebo in 40 patients with
of whom had sepsis. T ey found no MSC related hemody- moderate to severe ARDS. Angiopoietin 2 is a well-rec-
namic or respiratory adverse events within 6 h of infusion ognized mediator and biomarker of pulmonary and sys-
and no evidence for an increased risk of thromboembolic temic vascular injury. Angiopoietin-2 concentrations
events. However, the potential for MSCs to alter coagula- have important predictive value for the development of
tion and induce peripheral microthrombosis, pulmonary ARDS [232]. In addition, they robustly predict poor clini-
embolisms or severe cardiovascular events in high risk cal outcomes in adults and children with ARDS and are
patients demands that well-designed studies be conducted recognized as prognostic factors in patients with pneu-
to measure the safety of treatments that use MSCs derived monia [233–235]. T ere was a strong indirect correlation
from dif erent tissue sources. between cell viability and levels of angiopoietin-2, as well
as between viability and improvement in oxygenation
Human clinical trials of MSC therapy in acute index. Angiopoietin 2 levels in plasma showed a signif -
respiratory distress syndrome cantly greater decrease in the BM-MSC group than in
Zheng recently concluded a phase I, single center, dou- the placebo group [236, 237]. T e reductions in angi-
ble-blind, placebo-controlled trial assessing the safety opoietin-2 concentrations observed in this trial may be
of intravenous administration of allogeneic ASCs in related to the release of anti-inf ammatory mediators that
patients with ARDS [230]. Twelve patients with moderate can mitigate the lung injury. T e patients in the BM-MSC
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ARDS were randomized to receive one IV dose of 1 × 10 treatment group had higher disease severity scores than