The coronavirus disease 2019 (COVID-19) pandemic has been associated with hundreds of millions of hospitalizations and over 3.2 million deaths since it first emerged in late-2019. While the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results mostly in asymptomatic or mild disease, in about 15% of cases, patients become moderately or severely sick.
A recent study, published in Stem Cells Translational Medicine, explores the safety and efficacy of stem cells, which have been touted as the panacea for a wide range of illnesses, ranging from chronic degenerative conditions to cancer.
The severity of COVID-19 in some patients seems to be due to a hyper-inflammatory state resulting from a dysregulated immune response. This is characterized by a cytokine storm and immunologically-mediated clots. A distressing and often fatal complication of critical COVID-19 is acute respiratory distress syndrome (ARDS), frequently associated with multi-organ dysfunction.
The need now is for therapies to reduce the severity of inflammation which can cut short the vicious cycle that shortens the survival of these patients. Corticosteroids have been shown to be of significant use in specific conditions.
The use of stem cells in this scenario is argued to be of possible benefit by modulating immune responses in patients with severe COVID-19. The researchers in this study obtained umbilical cord mesenchymal stem cells (UC-MSCs), which can be quickly proliferated for clinical use and have been reported to be safe in other conditions.
These stem cells are not subject to ordinary host-graft incompatibility conditions, and have been used in various autoimmune and inflammatory diseases. Approval by the US Food and Drug Administration has been granted for the use of UC-MSCs for type 1 diabetes and Alzheimer’s disease.
Study aims and findings
Some studies have shown good results in patients with COVID-19 pneumonia who were treated with MSCs that do not express the host cell molecule angiotensin-converting enzyme 2 (ACE2) that serves as the receptor for the virus. This spurred the current investigation into the safety and effectiveness of UC-MSCs as a therapy for ARDS in COVID-19 patients.
Conducted as a blinded randomized controlled trial, it was designed as a phase 1/2a trial in 24 patients. Firstly, the use of these stem cells was observed to be safe. While over 90% of patients in the treatment group survived at 28 days from the last dose, only 42% in the control group did so.
Serious adverse effects were correspondingly low in the treatment group, at two, compared to 16 in the controls, and the former group also had a significantly shorter time to recovery.
The groups were roughly comparable in most comparators, but body mass index was significantly higher in the treatment group. Viral loads were comparable in both groups.
Possible explanations
The key effects of stem cell treatment are to reduce the levels of inflammatory mediators such as interferon (IFN)-γ, interleukin (IL)-6 and tumor necrotic factor (TNF)-α, which play a central role in the cytokine storm of COVID-19. Simultaneously, they reduce the levels of granulocyte-monocyte colony-stimulating factor (GM-CSF), the primary activator of the process by which monocytes are activated to become pro-inflammatory M1 macrophages. By so doing, they may shift the balance towards M2 macrophages that are activated by another pathway.
The levels of PDGF-BB (a type of platelet-derived growth factor with two B subunits), which powerfully stimulates cells of mesenchymal origin, were also reduced. This mediator enhances the activation of mesenchymal cells, stimulates the proliferation and migration of airway smooth muscle cells, increases cytokine production in lung fibroblasts and activates pain-sensing neurons.
Therefore, a reduction in PDGF-BB levels could mean that the MSC therapy speeds up the process of tissue repair, thus hastening recovery in the lungs, reducing the need for more PDGF-BB secretion.
What are the implications?
The study was very small, but the results do seem to show a strikingly beneficial effect of the use of UC-MSCs in this high-risk subset of COVID-19 patients on mortality and recovery. This warrants further research using a larger, more rigorous clinical trial.
Moreover, UC-MSCs could be used as part of a combined therapy, using corticosteroids with stem cells, for instance. The rationale is that as both agents seem to benefit patients at a similar stage of disease, the combination would be synergistic.
Viral loads are not noticeably reduced in the treatment group, indicating that the clinical response in these patients is due to the suppression of the over-secretion of inflammatory cytokines.
What are the conclusions?
These preliminary results indicate the utility and safety of UC-MSCs for ARDS in COVID-19 patients, with significant reductions in severe adverse events and deaths, and a faster recovery.
The observations made in this study could be of assistance for future studies in the field of COVID‐19, ARDS, hyperinflammatory states, overactive immune responses, and autoimmunity. In addition, the preferential targeting of lung tissue after intravenous infusion could make UC‐MSCs particularly appealing for ARDS secondary to trauma, microbial infection, and pulmonary GvHD.”
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