Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Mar 27, 2022; 13(2): 47-65
Published online Mar 27, 2022. doi: 10.4331/wjbc.v13.i2.47
Mesenchymal stromal cell delivery as a potential therapeutic strategy against COVID-19: Promising evidence from in vitro results
Panagiotis Mallis, Theofanis Chatzistamatiou, Zetta Dimou, Eirini-Faidra Sarri, Eleni Georgiou, Maria Salagianni, Vasiliki Triantafyllia, Evangelos Andreakos, Catherine Stavropoulos-Giokas, Efstathios Michalopoulos
Panagiotis Mallis, Theofanis Chatzistamatiou, Zetta Dimou, Eirini-Faidra Sarri, Eleni Georgiou, Catherine Stavropoulos-Giokas, Efstathios Michalopoulos, Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
Maria Salagianni, Vasiliki Triantafyllia, Evangelos Andreakos, Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
Author contributions: Mallis P designed the study, performed the experimental procedures and statistical analysis, and prepared the whole manuscript; Sarri EF, Dimou Z, and Georgiou E contributed to performing the experimental procedures; Salagianni M and Triantafyllia V contributed to performing the experimental procedures and data analysis; Michalopoulos E, Chatzistamatiou T, and Andreakos E made critical revisions related to the content of the manuscript; Stavropoulos-Giokas C and Michalopoulos E performed the final approval of the manuscript.
Institutional review board statement: The overall study has received approval from the Institution’s ethical board (Reference No. 1754, January 21, 2021).
Informed consent statement: The patient's legal guardian provided informed written consent prior to study enrollment.
Conflict-of-interest statement: All authors declare no conflict of interest for the current study.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Panagiotis Mallis, MSc, PhD, Associate Research Scientist, Teaching Assistant, Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, No. 4 Soranou Ephessiou Street, Athens 11527, Greece.
Received: November 6, 2021
Peer-review started: November 6, 2021
First decision: December 27, 2021
Revised: December 28, 2021
Accepted: March 6, 2022
Article in press: March 6, 2022
Published online: March 27, 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic, which was initiated in December 2019. COVID-19 is characterized by a low mortality rate (< 6%); however, this percentage is higher in elderly people and patients with underlying disorders. COVID-19 is characterized by mild to severe outcomes. Currently, several therapeutic strategies are evaluated, such as the use of anti-viral drugs, prophylactic treatment, monoclonal antibodies, and vaccination. Advanced cellular therapies are also investigated, thus representing an additional therapeutic tool for clinicians. Mesenchymal stromal cells (MSCs), which are known for their immunoregulatory properties, may halt the induced cytokine release syndrome mediated by SARS-CoV-2, and can be considered as a potential stem cell therapy.


To evaluate the immunoregulatory properties of MSCs, upon stimulation with COVID-19 patient serum.


MSCs derived from the human Wharton’s Jelly (WJ) tissue and bone marrow (BM) were isolated, cryopreserved, expanded, and defined according to the criteria outlined by the International Society for Cellular Therapies. Then, WJ and BM-MSCs were stimulated with a culture medium containing 15% COVID-19 patient serum, 1% penicillin-streptomycin, and 1% L-glutamine for 48 h. The quantification of interleukin (IL)-1 receptor a (Ra), IL-6, IL-10, IL-13, transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF)-a, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and indoleamine-2,3-dioxygenase (IDO) was performed using commercial ELISA kits. The expression of HLA-G1, G5, and G7 was evaluated in unstimulated and stimulated WJ and BM-MSCs. Finally, the interactions between MSCs and patients’ macrophages were established using co-culture experiments.


Thawed WJ and BM-MSCs exhibited a spindle-shaped morphology, successfully differentiated to “osteocytes”, “adipocytes”, and “chondrocytes”, and in flow cytometric analysis were characterized by positivity for CD73, CD90, and CD105 (> 95%) and negativity for CD34, CD45, and HLA-DR (< 2%). Moreover, stimulated WJ and BM-MSCs were characterized by increased cytoplasmic granulation, in comparison to unstimulated cells. The HLA-G isoforms (G1, G5, and G7) were successfully expressed by the unstimulated and stimulated WJ-MSCs. On the other hand, only weak expression of HLA-G1 was identified in BM-MSCs. Stimulated MSCs secreted high levels of IL-1Ra, IL-6, IL-10, IL-13, TGF-β1, FGF, VEGF, PDGF, and IDO in comparison to unstimulated cells (P < 0.05) after 12 and 24 h. Finally, macrophages derived from COVID-19 patients successfully adapted the M2 phenotype after co-culturing with stimulated WJ and BM-MSCs.


WJ and BM-MSCs successfully produced high levels of immunoregulatory agents, which may efficiently modulate the over-activated immune responses of critically ill COVID-19 patients.

Keywords: SARS-CoV-2, COVID-19, MSCs, Stem cell therapy, Cytokine storm, Immunomodulation

Core Tip: Coronavirus disease 2019 (COVID-19) is responsible for the acute respiratory distress syndrome occurrence, a disorder that might prove life-threatening for a great number of hospitalized patients. As an alternative to the already evaluated therapeutic protocols, mesenchymal stromal cells (MSCs) can be evaluated as a potential stem cell therapy. MSCs exert key immunoregulatory properties, either through direct or indirect contact. In the current study, stimulated Wharton’s Jelly and bone marrow-MSCs produced high levels of anti-inflammatory cytokines and growth factors and also efficiently performed the M2 phenotype switch of macrophages. Considering this data, MSCs could be considered as a valuable stem cell therapy for better COVID-19 management.