Coronavirus disease 2019 (COVID-19), the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which counts more than 650 million cases and more than 6.6 million of deaths worldwide, affects the respiratory system with typical symptoms such as fever, cough, sore throat, acute respiratory distress syndrome (ARDS), and fatigue. Other nonpulmonary manifestations are related with abnormal inflammatory response, the "cytokine storm", that could lead to a multiorgan disease and to death. Evolution of effective vaccines against SARS-CoV-2 provided multiple options to prevent the infection, but the treatment of the severe forms remains difficult to manage. The cytokine storm is usually counteracted with standard medical care and anti-inflammatory drugs, but researchers moved forward their studies on new strategies based on cell therapy approaches. The perinatal tissues, such as placental membranes, amniotic fluid, and umbilical cord derivatives, are enriched in mesenchymal stromal cells (MSCs) that exert a well-known anti-inflammatory role, immune response modulation, and tissue repair. In this review, we focused on umbilical-cord-derived MSCs (UC-MSCs) used in in vitro and in vivo studies in order to evaluate the weakening of the severe symptoms, and on recent clinical trials from different databases, supporting the favorable potential of UC-MSCs as therapeutic strategy.

1st Department of Internal Medicine Faculty of Medicine Comenius University University Hospital Bratislava 81499 Bratislava Slovakia

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava 03649 Martin Slovakia

Department of Neurosurgery and Brain Repair Morsani College of Medicine University of South Florida Tampa FL 33612 USA

PROMISE Department University of Palermo 90127 Palermo Italy

Research and Development Services Pradlacka 18 61300 Brno Czech Republic

Research Department IRCCS ISMETT 90127 Palermo Italy

Section of Histology and Embryology Department of Biomedicine Neurosciences and Advanced Diagnostics University of Palermo 90127 Palermo Italy

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