The major life-threatening symptoms of COVID-19 disease are the result of the dysregulation of the immune system, wherein the cascading release of cytokines, termed a cytokine storm, induces severe inflammation.
In past studies, stem cells have demonstrated immune-modulating properties, with the capacity to suppress T-cells, prevent the maturation of dendritic cells, lessen B-cell activation and proliferation, and inhibit the proliferation and cytotoxicity of natural killer cells.
Stem cell therapy has also been employed against viruses such as HIV, hepatitis B, and virus-associated acute respiratory distress syndrome (ARDS), a leading mortality factor in those with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
In a review paper recently uploaded to the journal Biomedicine & Pharmacotherapy by Mahendiratta et al. (May 2021) the applicability of stem cells in treating severe SARS-CoV-2 infection is investigated, with regard to ARDS therapy.
Stem cells interact with their surroundings via toll-like receptors on the cell's surface. When a virus interacts with these receptors, specific chemokines are released, resulting in an anti-inflammatory response.
Interaction of the toll-like receptors with inflammatory cytokines has also been suggested to result in the release of anti-inflammatory chemokines and soluble factors from stem cells, including nitric oxide, which induces cell cycle arrest of T-cells by repressing phosphorylation.
As the genome of the other significant coronaviruses besides SARS-CoV-2: SARS-CoV-1 and MERS-CoV, are generally similar, generate corresponding proteins, have a parallel mechanism of cell entry and replication, and result in the release of homologous pro-inflammatory cytokines, the group included these viruses in their literature review alongside SARS-CoV-2 and ARDS and in association with stem cell therapy.
In vitro and in vivo studies
Several in vitro studies into stem cell therapy for ARDS were examined, demonstrating enhanced wound healing, neutrophil migration or elimination, and restored permeability of pulmonary endothelial cells.
These studies demonstrate the potential value of stem cell therapy in the treatment of ARDS. However, the group could not find any relevant studies that specifically involved any of the coronaviruses of interest.
The in vivo studies reviewed by the group cover a much wider range of potential stem cell therapies, from vaccine platforms to inflammation attenuation by a range of mechanisms.
As a vaccine delivery vehicle, stem cells were programmed to express the SARS-CoV-2 spike protein, resulting in neutralizing antibody production not only against the spike protein but also the nucleocapsid protein. Stem cells have also been demonstrated to alleviate E. coli induced pneumonia via suppressed inflammation, improved arterial oxygenation, and reduction of bacterial load in rats.
Human trials that utilize stem cells against SARS-CoV-2 and ARDS are scarce, though the group sourced eleven that fit their search criteria and an additional 41 registered to begin. Among these most included critically ill COVID-19 patients that had developed ARDS, and preliminary results appear promising.
In one study, mesenchymal stem cells were transplanted into a patient intravenously with no adverse reactions, the individual then exhibiting increased oxygen saturation and a reduction in fever, testing negative for SARS-CoV-2 thirteen days after transplantation.
A decrease in pro-inflammatory cytokines and a correlating upregulation in anti-inflammatory signaling molecules was also observed. Other studies show similar results: an improvement in the PaO2/FiO2 ratio of those with ARDS, a reduction in neutrophil levels, alleviation of the cytokine storm, and normalization of T-cell counts.
These studies highlight the range and diversity of mechanisms utilized by stem cells to regenerate tissue, particularly in the restoration of lung function.
Many safety concerns regarding the use of stem cells are still in question, however, and in each of the above reviewed cases were only applied to critically ill patients that were unresponsive to conventional therapy.
Large and wide-scale clinical trials will be needed to properly assess the safety profile and applicability of stem cells to those with SARS-CoV-2, though combination with traditional antiviral treatments may prove a highly effective therapeutic strategy.
- Saniya Mahendiratta, Seema Bansal, Phulen Sarma, Harish Kumar, Gajendra Choudhary, Subodh Kumar, Ajay Prakash, Rakesh Sehgal, Bikash Medhi, Stem cell therapy in COVID-19: Pooled evidence from SARS-CoV-2, SARS-CoV, MERS-CoV and ARDS: A systematic review, Biomedicine & Pharmacotherapy, https://doi.org/10.1016/j.biopha.2021.111300, https://www.sciencedirect.com/science/article/pii/S0753332221000858