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

Abstract

Interleukin (IL)‐1 receptor antagonist (IL‐1Ra), a naturally occurring antagonist of IL‐1α/IL‐1β signaling pathways, has been attributed to the immunosuppressive effects of mesenchymal stem cells (MSCs). MSCs, in IL‐1Ra‐dependent manner, suppressed production of IL‐1β in dermal macrophages, induced their polarization in anti‐inflammatory M2 phenotype, attenuated antigen‐presenting properties of dendritic cells (DCs), and promoted expansion of immunosuppressive T regulatory cells in the skin, which resulted in enhanced repair of the nonhealing wounds. Reduced activation of inflammasome and suppressed production of IL‐1β in macrophages were mainly responsible for beneficial effects of MSC‐derived IL‐1Ra in alleviation of acute lung injury, dry eye syndrome, and corneal injury. Through the production of IL‐1Ra, MSCs reduced migration of DCs to the draining lymph nodes and attenuated generation of inflammatory Th1 and Th17 cells that resulted in alleviation of fulminant hepatitis and rheumatoid arthritis. MSCs, in IL‐1Ra‐dependent manner, reduced liver fibrosis by suppressing production of Type I collagen in hepatic stellate cells. IL‐1Ra was, at least partially, responsible for enhanced proliferation of hepatocytes and chondrocytes in MSC‐treated animals with partial hepatectomy and osteoarthritis. Despite of these beneficial effects, IL‐1Ra‐dependent inhibition of IL‐1α/IL‐1β‐signaling significantly increased risk of infections. Therefore, future experimental and clinical studies should delineate potential side effects of MSC‐derived IL‐1Ra before IL‐1Ra‐overexpressing MSCs could be used as a potentially new therapeutic agent for the treatment of acute and chronic inflammatory diseases.

Mechanisms of interactions between lung‐origin telocytes and mesenchymal stem cells to treat experimental acute lung injury

“…To investigate whether TCs can increase the migration of MSCs from the peritoneal cavity to the lung, we observed the indirect interaction between MSCs and TCs by measuring migration of MSCs pre‐activated with LPS or vehicle from the upper chamber to the low one where TCs pre‐activated with LPS or vehicle. The better efficacy of MSCs and TCs may depend upon cell migration and specific homing towards the site where the cells are needed 26 . To investigate whether TCs can increase MSCs capacities of migration and infiltration, we measured migrated numbers of MSCs from upper chamber to lower one where TCs were located, in conditions of pre‐activated MSCs or TCs cultured alone or co‐culture.…”

“…The better efficacy of MSCs and TCs may depend upon cell migration and specific homing towards the site where the cells are needed. 26 To investigate whether TCs can increase MSCs capacities of migration and infiltration, we measured migrated numbers of MSCs from upper chamber to lower one where TCs were located, in conditions of pre-activated MSCs or TCs cultured alone or co-culture. Co-cultured TCs could increase MSCs capacities of migration and infiltration, especially when either TCs or MSCs were pre-activated with LPS ( Figure 5A,B).…”

Proposed Mechanisms of Targeting COVID-19 by Delivering Mesenchymal Stem Cells and Their Exosomes to Damaged Organs

“…As a result, MSC-secreted IL-1Ra suppresses immune cell infiltration into the lung. Under the effect of IL-1Ra, MSCs secrete VEGF, which increases type II surfactantsecreting alveolar cell regeneration and prevents endothelial cell apoptosis [76]. MSC therapy modulates immune response and decreases lung tissue fibrosis in ALI/ARDS in vivo models [71,[77][78][79] Considering the immunomodulatory effects of MSCs, they prevent and eliminate cytokine storm in COVID-19 and decrease life-threatening complications.…”

Therapeutic Applications of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis

“…In addition, by direct mitochondrial transfer via connexin-mediated intercellular channels or EVs from MSCs to the damaged cells, MSCs can restore the ATP storage in recipient cells and repair cell functions (Morrison et al, 2017;Paliwal et al, 2018). For their immunomodulatory role, MSCs express a set of injury and molecular pathogen receptors, such as Toll-like receptors (Shirjang et al, 2017), and release a series of cytokines and chemokines, such as IL-1 receptor antagonist (IL-1RA) (Harrell et al, 2020) and soluble TNF receptor 1 (sTNFR1) (Ding et al, 2019), which have anti-inflammatory effects. Intercellular contact molecules or MSC-secreted soluble factors regulate the adaptive and innate immune system by inhibiting the maturation of T cells and dendritic cells, reducing B cell activation and proliferation, and inhibiting the cytotoxicity of natural killer cells (Ni et al, 2018;de Castro et al, 2019;He et al, 2020).…”