Mesenchymal Stem Cells Reconditioned in Their Own Serum Exhibit Augmented Therapeutic Properties in the Setting of Acute Respiratory Distress Syndrome

Abstract

Mesenchymal stem cells (MSCs) are a promising form of therapy for acute respiratory distress syndrome (ARDS). The objective of this study was twofold: (a) to characterize cytokine expression in serum from ARDS subjects receiving MSCs and (b) to determine MSC function following “preconditioning” with ARDS serum. In phase I, serum from three cohorts of animals (uninjured [no ARDS, n = 4], injured untreated [n = 5], and injured treated with approximately 6 million per kilogram MSCs [n = 7]) was analyzed for expression of inflammatory mediators. In phase II, the functional properties of bone marrow porcine MSCs were assessed following “preconditioning” with serum from the three cohorts. In phase III, the findings from the previous phases were validated using human bone marrow MSCs (hBM‐MSCs) and lipopolysaccharide (LPS). Serum from injured treated animals had significantly lower levels of interferon‐γ and significantly higher levels of interleukin (IL)‐1 receptor antagonist (IL‐1RA) and IL‐6. Similarly, upon exposure to the injured treated serum ex vivo, the MSCs secreted higher levels of IL‐1RA and IL‐10, dampened the secretion of proinflammatory cytokines, exhibited upregulation of toll‐like receptor 4 (TLR‐4) and vascular endothelial growth factor (VEGF) genes, and triggered a strong immunomodulatory response via prostaglandin E2 (PGE2). hBM‐MSCs demonstrated a similar augmented therapeutic function following reconditioning in a LPS milieu. Administration of MSCs modulated the inflammatory milieu following ARDS. Exposure to ARDS serum ex vivo paralleled the trends seen in vivo, which appear to be mediated, in part, through TLR‐4 and VEGF and PGE2. Reconditioning MSCs in their own serum potentiates their immunotherapeutic function, a technique that can be used in clinical applications. Stem Cells Translational Medicine 2019;8:1092–1106

The role of Interleukin 1 receptor antagonist in mesenchymal stem cell‐based tissue repair and regeneration

“…Intravenous injection of IL‐1Ra‐producing MSCs completely attenuated lung inflammation in mice by suppressing the production of TNF‐α, IL‐1α, and IL‐1β in alveolar macrophages resulting in alleviated influx of circulating neutrophils and lymphocytes in BLM‐injured lungs . The highest production of IL‐1Ra by lung‐infiltrated MSCs was observed 72 hr after lung injury and was mainly triggered by IL‐6, released from lung‐infiltrated neutrophils and alveolar macrophages . Importantly, as revealed by Xu and colleagues, MSC‐derived IL‐1Ra creates “positive autocrine loop” in population of lung‐infiltrated MSCs by promoting their expansion and capacity for neovascularization, bacterial clearance, and immunosuppression .…”

“…54 The highest production of IL-1Ra by lunginfiltrated MSCs was observed 72 hr after lung injury and was mainly triggered by IL-6, released from lunginfiltrated neutrophils and alveolar macrophages. 53,56,57 Importantly, as revealed by Xu and colleagues, MSCderived IL-1Ra creates "positive autocrine loop" in population of lung-infiltrated MSCs by promoting their expansion and capacity for neovascularization, bacterial clearance, and immunosuppression. 53,55 Under the influence of IL-1Ra, MSCs upregulate the expression of vascular endothelial growth factor (VEGF) that prevents the apoptosis of endothelial cells, induces neovascularization, and promotes regeneration of injured alveolar Type II epithelial cells.…”

Mesenchymal stem cells as a potential treatment for critically ill patients with coronavirus disease 2019

“…1 Notably, it has been proved that MSC-released cytokines can potently inhibit neutrophil intravasation and enhance the differentiation of macrophages. 5,6 Moreover, these MSC-released EVs can deliver microRNA, mRNA, DNA, proteins, and metabolites into host cells in specific injuries of the lung to promote lung repair as well as regeneration and restore lung function. 1 As the continuing epidemic threat of SARS-CoV-2 to global health and the fast-growing number of fatalities, advancing new therapeutic development becomes central or primary to minimize the death and sequelae from SARS-CoV-2 infection.…”

Can mesenchymal stem cells be used to treat COVID‑19‑induced pneumonia? (Review)

“…1) (68). Notably, it has been shown that cytokines released by MSCs may potently inhibit neutrophil intravasation and enhance the differentiation of macrophages (69,70).…”