Umbilical Cord-derived Mesenchymal Stem Cells modulate TNF and soluble TNF Receptor 2 (sTNFR2) in COVID-19 ARDS patients

D. Kouroupis, G. Lanzoni, E. Linetsky, S. Messinger Cayetano, S. Wishnek Metalonis, C. Leñero, L.D. Stone, P. Ruiz, D. Correa, C. Ricordi

Department of Orthopedics, UHealth Sports Medicine Institute, University of Miami Miller School of Medicine, Miami, FL, USA. ricordi@miami.edu

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• Infectious Diseases

OBJECTIVE: We aimed at explaining the mechanism of therapeutic effect of Umbilical Cord Mesenchymal Stem Cells (UC-MSC) in subjects with COVID-19 Acute Respiratory Distress Syndrome (ARDS). Patients with COVID-19 ARDS present with a hyperinflammatory response characterized by high levels of circulating pro-inflammatory mediators, including tumor necrosis factor α and β (TNFα and TNFβ). Inflammatory functions of these TNFs can be inhibited by soluble TNF Receptor 2 (sTNFR2). In patients with COVID-19 ARDS, UC-MSC appear to impart a robust anti-inflammatory effect, and treatment is associated with remarkable clinical improvements. We investigated the levels of TNFα, TNFβ and sTNFR2 in blood plasma samples collected from subjects with COVID-19 ARDS enrolled in our trial of UC-MSC treatment.

PATIENTS AND METHODS: We analyzed plasma samples from subjects with COVID-19 ARDS (n=24) enrolled in a Phase 1/2a randomized controlled trial of UC-MSC treatment. Plasma samples were obtained at Day 0 (baseline, before UC-MSC or control infusion), and Day 6 post infusion. Plasma concentrations of sTNFR2, TNFα, and TNFβ were evaluated using a quantitative multiplex protein array.

RESULTS: Our data indicate that at Day 6 after infusion, UC-MSC recipients develop significantly increased levels of plasma sTNFR2 and significantly decreased levels of TNFα and TNFβ, compared to controls.

CONCLUSIONS: These observations suggest that sTNFR2 plays a mechanistic role in mediating UC-MSC effect on TNFα and TNFβ plasma levels, determining a decrease in inflammation in COVID-19 ARDS.

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