Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients

Abstract

In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan, capital city of Hubei province in China. Cases of SARS-CoV-2 infection quickly grew by several thousand per day. Less than 100 days later, the World Health Organization declared that the rapidly spreading viral outbreak had become a global pandemic. Coronavirus disease 2019 (COVID-19) is typically associated with fever and respiratory symptoms. It often progresses to severe respiratory distress and multi-organ failure which carry a high mortality rate. Older patients or those with medical comorbidities are at greater risk for severe disease. Inflammation, pulmonary edema and an over-reactive immune response can lead to hypoxia, respiratory distress and lung damage. Mesenchymal stromal/stem cells (MSCs) possess potent and broad-ranging immunomodulatory activities. Multiple in vivo studies in animal models and ex vivo human lung models have demonstrated the MSC's impressive capacity to inhibit lung damage, reduce inflammation, dampen immune responses and aid with alveolar fluid clearance. Additionally, MSCs produce molecules that are antimicrobial and reduce pain. Upon administration by the intravenous route, the cells travel directly to the lungs where the majority are sequestered, a great benefit for the treatment of pulmonary disease. The in vivo safety of local and intravenous administration of MSCs has been demonstrated in multiple human clinical trials, including studies of acute respiratory distress syndrome (ARDS). Recently, the application of MSCs in the context of ongoing COVID-19 disease and other viral respiratory illnesses has demonstrated reduced patient mortality and, in some cases, improved long-term pulmonary function. Adipose-derived stem cells (ASC), an abundant type of MSC, are proposed as a therapeutic option for the treatment of COVID-19 in order to reduce morbidity and mortality. Additionally, when proven to be safe and effective, ASC treatments may reduce the demand on critical hospital resources. The ongoing COVID-19 outbreak has resulted in significant healthcare and socioeconomic burdens across the globe. There is a desperate need for safe and effective treatments. Cellular based therapies hold great promise for the treatment of COVID-19. This literature summary reviews the scientific rationale and need for clinical studies of adipose-derived stem cells and other types of mesenchymal stem cells in the treatment of patients who suffer with COVID-19.

Single-Cell Transcriptomic Attributes and Unbiased Computational Modeling for the Prediction of Immunomodulatory Potency of Mesenchymal Stromal Cells

“…These cytokines are known to be elevated as a result of cytokine storm due to the activation of innate immune cells, including macrophages during acute viral and bacterial infection (e.g., SARS-COV-2 infection (21,22), sepsis (23,24)), and BM and CT-MSCs (both OOT and CR products) may mitigate the hyperinflammation by inhibiting the cytokine response of macrophages (25,26). In T cell proliferation assay, OOT MSCs showed very low or no suppression as compared to CR MSCs for both BM and CT MSCs.…”

Research progress on Mesenchymal Stem Cells (MSCs), Adipose-Derived Mesenchymal Stem Cells (AD-MSCs), Drugs, and Vaccines in Inhibiting COVID-19 Disease

“…There have been reports of serious complications caused by the improper application of MSCs in the past [28]. Donor-specific antibodies have been observed in 19-34% of patients receiving allogeneic AD-MSCs infusion suggesting that a cellular response can occur [29]. On the other hand, no clinical immune reactions have been seen in studies that have used intravenous AD-MSCs (1×10 6 ASCs/kg) as reported in a recent review [29].…”

“…These results provide important insights into A-Se-MiRs function and could suggest their use as anti-viral. On the basis of the mentioned above concepts, ASCs treatments may reduce the demand for critical hospital resources [29].…”

“…Donor-specific antibodies have been observed in 19-34% of patients receiving allogeneic AD-MSCs infusion suggesting that a cellular response can occur [29]. On the other hand, no clinical immune reactions have been seen in studies that have used intravenous AD-MSCs (1×10 6 ASCs/kg) as reported in a recent review [29]. First-line doctors should formulate individualized treatment plans according to the patient's situation, such as cell dosage, cell suspension concentration, and infusion speed, so as to ensure the maximum curative effect.…”

Cell-Free Therapies: Novel Approaches for COVID-19

“…EV biochemistry varies according to composition and cell source (41). EVs can carry membrane and cytosolic proteins, transcription factors, DNA, coding and non-coding RNAs and various signal transduction molecules (5,21,38,42), acting on both physiological and pathological events, e.g., modulating the inflammatory response (2,14). EVs also carry different cytokines and growth factors, such as interleukin (IL)-6 and IL-10, transforming growth factor (TGF)-β, and hepatocyte growth factor (HGF) (43).…”