Mesenchymal Stem Cells Derived Extracellular Vesicles Alleviate Traumatic Hemorrhagic Shock Induced Hepatic Injury via IL-10/PTPN22-Mediated M2 Kupffer Cell Polarization

Abstract

Traumatic hemorrhagic shock (THS) is a major cause of mortality and morbidity worldwide in severely injured patients. Mesenchymal stem cells (MSCs) possess immunomodulatory properties and tissue repair potential mainly through a paracrine pathway mediated by MSC-derived extracellular vesicles (MSC-EVs). Interleukin 10 (IL-10) is a potent anti-inflammatory cytokine that plays a crucial role during the inflammatory response, with a broad range of effects on innate and adaptive immunity, preventing damage to the host and maintaining normal tissue homeostasis. However, the function and mechanism of IL-10 in MSC-mediated protective effect in THS remain obscure. Here, we show that MSCs significantly attenuate hepatic injury and inflammation from THS in mice. Notably, these beneficial effects of MSCs disappeared when IL-10 was knocked out in EVs or when recombinant IL-10 was administered to mice. Mechanistically, MSC-EVs function to carry and deliver IL-10 as cargo. WT MSC-EVs restored the function of IL-10 KO MSCs during THS injury. We further demonstrated that EVs containing IL-10 mainly accumulated in the liver during THS, where they were captured by Kupffer cells and induced the expression of PTPN22. These effects subsequently shifted Kupffer cells to an anti-inflammatory phenotype and mitigated liver inflammation and injury. Therefore, our study indicates that MSC-EVs containing IL-10 alleviate THS-induced hepatic injury and may serve as a cell-free therapeutic approach for THS.

IL-10 partly mediates the ability of MSC-derived extracellular vesicles to attenuate myocardial damage in experimental metabolic renovascular hypertension

“…Our observations implying that IL-10 is a central mediator of the anti-inflammatory properties of EVs in the myocardium are consistent with previous studies suggesting that IL-10-overexpressing MSCs increased autophagy and protected rats against traumatic brain injury-induced neuronal damage ( 39 ). Additionally, MSC-derived EVs alleviated hepatic injury via IL-10-mediated M2 Kupffer cell polarization ( 40 ). Congruently, M2 reparative macrophages release high levels of anti-inflammatory IL-10 ( 41 ).…”

Global scientific trends on the immunomodulation of mesenchymal stem cells in the 21st century: A bibliometric and visualized analysis

“…MSCs significantly promote tissue regeneration by regulating the subtype distribution and phenotypes of immune cells, including macrophage polarization ( 29 ). Moreover, MSCs immunosuppress inflammatory response in the early phase of tissue injury, resulting in less scarring and tissue regeneration ( 30 ). The immunomodulatory properties of MSCs also rely on the paracrine effects, including cytokines and extracellular vesicles ( 31 , 32 ).…”

Mesenchymal Stem Cells and Their Small Extracellular Vesicles as Crucial Immunological Efficacy for Hepatic Diseases

“…A significant decline in the M1/M2 MF ratio is observed following MSC or MSC-sEV treatment (73). Mechanistically, TGF-b secreted by MSCs facilitates the polarization of CD163 + M2 MF through the Akt/FoxO1 pathway (74), while MSC-sEVs deliver IL-10 to Kupffer cells and induce the expression of PTPN22, shifting Kupffer cells to an anti-inflammatory phenotype and mitigating liver inflammation (75). Enrichment of miRNA in MSC-sEVs negatively regulates the inflammatory environment by miR-223-3p targeting stathmin 1 (76), miR-21 targeting programmed cell death 4 (77), and miR-124-3p targeting nucleus signaling 1 (78).…”