**9. Conclusions and Perspectives**

The present global health crisis involving the appearance and rapid spread of a new coronavirus has encouraged the worldwide scientific community to consider how it can help to combat this mounting viral pandemic.

Amongst all the different mesenchymal stromal/stem cells that might be used, umbilical cord stem cells seem to be the most desirable for a series of reasons that have been very well explained by S. Atluri et al. [81]. Considering together both the previous reports and our own knowledge, and research on the exceptional abilities of proliferation [5,7], secretion [4] and differentiation [17,71] of the umbilical cord mesenchymal stromal/stem cells that we have investigated [7,8], we have also decided to recommend umbilical cord mesenchymal stromal/stem cells as a vehicle for annexin A1 for septic shock treatment.

The activation of these MSCs with a 2 Gy low-LET radiation dose produces an important increase in the cell-released exosomes and these nanovesicles, which can reach all the tissues and organs affected, contain a very specific load of proteins, including annexin A1 [8,12], whose activity in situations of infection, inflammation and hypoxia has been intensively discussed in the previous sections of this paper. This protein together with the endothelium-repair functions characteristic of MSCs must play a major role in the treatment of the septic shock and pneumonia related with SARS-CoV-2 infection.

Moreover, it is generally accepted that the efficacy of transplanted MSCs actually seems to be independent of the physical proximity of the transplanted cells to damaged tissue. Supposedly a vectorized signaling system, we now believe that the exosomes released from radiation-activated-MSCs cells can reach other organs different from the lungs, where they will be up-taken after intravenous injection and thus extend the anti-inflammatory and antimicrobiological effects of the treatment, to cover systemic problems such as the treatment of patients with septic shock in general and for COVID-19 at this particular time.

This hypothesis provides a rationale for the therapeutic efficacy of MSCs and their secreted exosomes in patients with clinical conditions characterized by respiratory failure necessitating mechanical ventilation and medical assistance in the intensive care unit, for multiorgan insufficiency and systemic manifestations such as sepsis, septic shock and multiple organ dysfunction cases.

Lastly, a scheme for our hypothetical cellular therapy in patients with acute respiratory distress syndrome would be an intravenous infusion of 6 million/kg of patient-weight divided into two parts: (a) 3 million nonirradiated-MSCs/kg of patient-weight, to take advantage of the protective, regenerative and repair MSCs-effects at the lung–vasculature and (b) 3 million preirradiated-MSCs\*/kg of patient-weight, to achieve, as soon as possible within the patients, the loaded-exosomes with ANXA1 that clinical-grade umbilical cord MSCs\* are able to produce after radiation stimulation and thus, take advantage of the extensive range of anti-thrombo-inflammatory, antiviral and immunomodulatory actions associated with this protein.

Finally, we want to clarify that this paper only presents a hypothesis and that the possibility of treating patients is still far off because we lack the necessary experimental data, which would prove the applicability, efficiency and security necessary to further the hypothesis in its transition from the laboratory bench to the patient's bed. Therefore, more work is necessary to promote this idea and use activated MSCs\* as a therapy for patients with COVID-19, but that is our challenge and we are optimistic of a positive outcome.

**Author Contributions:** I.T., R.G., J.J.L.-P., J.E. and J.M.R.d.A. contributed to the study conception and design. The first draft of the manuscript was written by J.M.R.d.A. and all authors commented on previous versions of the manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by Ministerio de Economía y Competividad, MINECO: SAF2012-40011-C02-02 and SAF2015-70520-R, RTICC RD12/0036/0026 to J.M.R.d.A.

**Acknowledgments:** The authors thank A.L. Tate for revising their English text.

**Conflicts of Interest:** The authors declare no conflict of interest.
