Extracellular Vesicles From Adipose Tissue-Derived Stem Cells Affect Notch-miR148a-3p Axis to Regulate Polarization of Macrophages and Alleviate Sepsis in Mice

Abstract

Extracellular vesicles (EVs) from adipose tissue-derived stem cells have been reported to attenuate lipopolysaccharide (LPS) induced inflammation and sepsis while the specific mechanism is unclear. This study explored the underlying molecular mechanisms of EVs from adipose tissue-derived stem cells in reducing inflammation. LPS- induced macrophage models and mice model were established to mimic inflammation in vitro and in vivo . EVs were extracted from adipose tissue-derived stem cells and identified. It was found that proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, substantially decreased after EVs were applied to LPS-stimulated macrophages and mice, and thus, LPS induced M1 polarization was inhibited and sepsis was strongly alleviated. In the LPS induced macrophages, the expression of Notch signaling molecules and the activation of the NF-κB pathway were substantially decreased after the administration of EVs. Then, RBP-J −/− mice and macrophages were used. It was found that the miR-148a-3p level was significantly lower in the RBP-J −/− macrophages than in the wildtype macrophages. In the LPS induced macrophages, the increasing of miR-148a-3p was milder in the RBP-J −/− macrophages than in the wild type macrophages. Then, miR-148a-3p was overexpressed in macrophages and mice, and we found that the expression of proinflammatory cytokines was increased both in vivo and in vitro . The protective effect of EVs in LPS induced sepsis was diminished by the overexpression of miR-148a-3p. In conclusion, we proved that EVs could attenuate inflammation and further protect organ function by regulating the Notch-miR148a-3p signaling axis and then decreasing macrophage polarization to M1.

Macrophage Polarization and Its Role in Liver Disease

“…Similarly, miR-148a-3p was shown to be a mediator by which Notch promotes M1 polarization ( 80 ). Moreover, adipose stem cell-derived extracellular vesicles (EVs) could inhibit the Notch signaling pathway and M1 polarization to exert anti-inflammatory effects, which was associated with decreased expression of miR148a-3p ( 81 ).…”

Therapeutic Application of Exosomes in Inflammatory Diseases

“…It affects 20 million patients worldwide each year and accounts for a large portion of the mortality rate [ 141 ]. Several studies have found that MSC-derived EVs lowered systemic inflammation and alleviated organ damage in sepsis [ 142 , 143 , 144 ]. EVs from healthy AD-MSCs reduced the circulating level of TNF-α, and this led to a significant increase in the survival rate in a rat model of sepsis [ 142 ].…”

“…Another group examined the effect of AD-MSC-derived EVs on sepsis in mice. They administered AD-MSC-derived EVs and observed regulation of LPS-induced inflammation via the Notch-miR-148a-3p axis and consequent relief of sepsis [ 143 ]. In a recent study, super-repressor IκB (srIκB, a dominant active form of IκBα) was loaded into EVs, and the effect on sepsis-associated organ damage and mortality was observed [ 144 ].…”

Stem Cell-Derived Extracellular Vesicles as Potential Therapeutic Approach for Acute Kidney Injury

“…In experimental models of sepsis obtained by LPS administration or by cecal ligation and puncture (CLP) MSC-derived EVs inhibited the development of disease by downregulating JMJD3 and inactivating the NF-κB signaling pathway through the selected transfer of miR-27b ( 122 ). EVs isolated from AD-MSCs have been shown to attenuate inflammation and protect from organ dysfunction by regulating the Notch-miR148a-3p signaling axis and decreasing macrophage polarization to M1 ( 123 ). In experimental s-AKI, the administration of EVs isolated from AD-MSCs exerted a renal protective effect through SIRT1 signaling pathway ( 124 ).…”