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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.

SUBMITTER: Tovar I

PROVIDER: S-EPMC7565018 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Tovar Isabel I Guerrero Rosa R López-Peñalver Jesús J JJ Expósito José J Ruiz de Almodóvar José Mariano JM

Cells 20200902 9

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 cell ...[more]

PMID: 32887260

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Project description:Mesenchymal stromal cells (MSCs) have been investigated as a treatment for various inflammatory diseases because of their immunomodulatory and reparative properties. However, many basic questions concerning their mechanisms of action after systemic infusion remain unanswered. We performed a detailed analysis of the immunomodulatory properties and proteomic profile of MSCs systemically administered to two patients with severe refractory acute respiratory distress syndrome (ARDS) on a compassionate use basis and attempted to correlate these with in vivo anti-inflammatory actions. Both patients received 2×10(6) cells per kilogram, and each subsequently improved with resolution of respiratory, hemodynamic, and multiorgan failure. In parallel, a decrease was seen in multiple pulmonary and systemic markers of inflammation, including epithelial apoptosis, alveolar-capillary fluid leakage, and proinflammatory cytokines, microRNAs, and chemokines. In vitro studies of the MSCs demonstrated a broad anti-inflammatory capacity, including suppression of T-cell responses and induction of regulatory phenotypes in T cells, monocytes, and neutrophils. Some of these in vitro potency assessments correlated with, and were relevant to, the observed in vivo actions. These experiences highlight both the mechanistic information that can be gained from clinical experience and the value of correlating in vitro potency assessments with clinical effects. The findings also suggest, but do not prove, a beneficial effect of lung protective strategies using adoptively transferred MSCs in ARDS. Appropriate randomized clinical trials are required to further assess any potential clinical efficacy and investigate the effects on in vivo inflammation.This article describes the cases of two patients with severe refractory adult respiratory syndrome (ARDS) who failed to improve after both standard life support measures, including mechanical ventilation, and additional measures, including extracorporeal ventilation (i.e., in a heart-lung machine). Unlike acute forms of ARDS (such in the current NIH-sponsored study of mesenchymal stromal cells in ARDS), recovery does not generally occur in such patients.

Dataset Information

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

Publications

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

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