**1. Introduction**

The investigation into mesenchymal stromal/stem cells (MSCs) has been of outstanding interest in the recent years [1]. Stromal cells are heterogeneous and contain several populations, including stem cells with different multipotential properties, committed progenitors and differentiated cells [2]. In all our experiments, we have used MSCs obtained from the human umbilical cord perivascular area of Wharton's jelly [3]. We have described these cells and assessed their phenotype [3], self-renewal potential, contractibility, differentiation [3–5], clonogenicity, radiosensitivity [6], secretion [5] and antitumoral activity both in basal conditions and after stimulation with X-rays [7,8].

We have recently shown that the combination of human umbilical-cord-derived MSCs cell therapy plus radiotherapy significantly reduces the size of established tumors in mice, both in the directly irradiated tumor and in the distant nonirradiated tumor [7] or in its metastasis [8]. These results support the hypothesis that human mesenchymal stromal/stem cells are radiosensitizers for local tumor radiotherapy, and simultaneously, they represent an effective tool for amplifying the systemic effects of radiotherapy. These out-of-target radiotherapy effects [9–11], promoted by MSCs are, in our view, of major interest [9,12].

We have also proved [7,8], that the preirradiation of MSCs triggers an important cellular change that transforms the MSCs into a source of molecules with very interesting pharmacologic proprieties. Amongst these actively secreted molecules, we have identified TRAIL and Dkk3 with very well-known antitumor activities, and annexin A1, whose activities we have previously reviewed [12] and now update here to include new data that demonstrate its anti-inflammatory and antiviral activity and its role in the regulation of hypoxia.

This secretion activity suggests a mechanistic explanation of how activated cells may positively spread their effect far from the place where they are applied. On this basis, we believe that exosomes, heavily loaded with annexin A1, will be liberated in the lungs after cell therapy with irradiated-MSCs cells, and this action would ameliorate symptoms in patients with sepsis in the lungs and in any other organs affected by septic shock.

A significant number of scientific reports are available demonstrating that gap junction, paracrine pathways and exocrine effects can transmit radiation-induced biological effects far from the place where the radiation is applied. These effects are frequently referred to as radiation-induced out-of-target effects. Multiple molecular signaling mechanisms [13] involving oxidative stress [14,15], kinases, inflammatory molecules [16,17], exosomes [8], microvesicles are postulated to contribute to bystander short- and long-range effects [12]. The anticancer immune response may also be activated by ionizing radiation, and a combination of different treatment strategies is promising in this field [11,18]. The activation of the immune system by the irradiated tumor to trigger the beneficial abscopal effect is decisively improving radiotherapy applications and their outcomes [19–22].
