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

**Isabel Tovar 1,2, Rosa Guerrero 1,2, Jesús J. López-Peñalver <sup>3</sup> , José Expósito 1,2,4 and José Mariano Ruiz de Almodóvar 5,\***


Received: 31 July 2020; Accepted: 31 August 2020; Published: 2 September 2020

**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.

**Keywords:** experimental radiotherapy; radiobiology; mesenchymal stem cells; cell therapy; exosome; annexin A1; acute respiratory-distress syndrome; COVID-19
