Rationale for the Use of Radiation-Activated Mesenchymal Stromal/Stem Cells in Acute Respiratory Distress Syndrome

Abstract

We have previously shown that the combination of radiotherapy with human umbilical-cord-derived mesenchymal stromal/stem cells (MSCs) cell therapy significantly reduces the size of the xenotumors in mice, both in the directly irradiated tumor and in the distant nonirradiated tumor or its metastasis. We have also shown that exosomes secreted from MSCs preirradiated with 2 Gy are quantitatively, functionally and qualitatively different from the exosomes secreted from nonirradiated mesenchymal cells, and also that proteins, exosomes and microvesicles secreted by MSCs suffer a significant change when the cells are activated or nonactivated, with the amount of protein present in the exosomes of the preirradiated cells being 1.5 times greater compared to those from nonirradiated cells. This finding correlates with a dramatic increase in the antitumor activity of the radiotherapy when is combined with MSCs or with preirradiated mesenchymal stromal/stem cells (MSCs*). After the proteomic analysis of the load of the exosomes released from both irradiated and nonirradiated cells, we conclude that annexin A1 is the most important and significant difference between the exosomes released by the cells in either status. Knowing the role of annexin A1 in the control of hypoxia and inflammation that is characteristic of acute respiratory-distress syndrome (ARDS), we designed a hypothetical therapeutic strategy, based on the transplantation of mesenchymal stromal/stem cells stimulated with radiation, to alleviate the symptoms of patients who, due to pneumonia caused by SARS-CoV-2, require to be admitted to an intensive care unit for patients with life-threatening conditions. With this hypothesis, we seek to improve the patients’ respiratory capacity and increase the expectations of their cure.

Anti-Tumor Effects of Exosomes Derived from Drug-Incubated Permanently Growing Human MSC

“…As with X-rays, exposure of MSC to UV light [44] or heat [45] induces increased release of anti-tumor or immunogenic factors, such as TNF-α and IFN-γ. In addition, enhanced production of annexin A1 in radiotherapy-stimulated MSC can relay anti-tumor signals [46,47]. This may provide superior therapeutic effectiveness by a combined stimulation of MSC with radiotherapy and drugs.…”

Immunoregulatory therapy strategies that target cytokine storms in patients with COVID‑19 (Review)

“…Some of these drugs exert therapeutic efficacies that are associated with regulation of the immune system. In addition, since MSCs have an immunosuppressive effect, and associated clinical trial data have shown significant therapeutic efficacy in severe cases of COVID-19 (78)(79)(80), MSC-based therapy could be a promising strategy for the reduction of inflammatory cytokine release in these patients. Therefore, we hypothesize that immunoregulatory therapy is currently the most promising treatment for severe COVID-19, especially for the elderly patients or those with underlying diseases.…”

Enhancement strategies for mesenchymal stem cells and related therapies

“…The authors report on key components of cell–cell or cell–matrix adhesion, including annexins and integrins, and link it with enhanced tumor cell death. It was also noted that the amount of protein present in pre-irradiated cells was 1.5 times greater compared to nonirradiated controls and this finding correlated with enhanced anti-tumor activity when combined with radiation therapy [ 84 ].…”