MSC-derived exosomes attenuate hepatic fibrosis in primary sclerosing cholangitis through inhibition of Th17 differentiation.

Primary sclerosing cholangitis (PSC) is an autoimmune cholangiopathy characterized by chronic inflammation of the biliary epithelium and periductal fibrosis, with no curative treatment available, and liver transplantation is inevitable for end-stage patients. Human placental mesenchymal stem cell (hpMSC)-derived exosomes have demonstrated the ability to prevent fibrosis, inhibit collagen production and possess immunomodulatory properties in autoimmune liver disease. Here, we prepared hpMSC-derived exosomes (ExoMSC) and further investigated the anti-fibrotic effects and detailed mechanism on PSC based on Mdr2-/- mice and multicellular organoids established from PSC patients. The results showed that ExoMSC ameliorated liver fibrosis in Mdr2-/- mice with significant collagen reduction in the preductal area where Th17 differentiation was inhibited as demonstrated by RNAseq analysis, and the percentage of CD4+IL-17A+T cells was reduced both in ExoMSC-treated Mdr2-/- mice (Mdr2-/--Exo) in vivo and ExoMSC-treated Th17 differentiation progressed in vitro. Furthermore, ExoMSC improved the hypersecretory phenotype and intercellular interactions in the hepatic Th17 microenvironment by regulating PERK/CHOP signaling as supported by multicellular organoids. Thus, our data demonstrate the anti-fibrosis effect of ExoMSC in PSC disease by inhibiting Th17 differentiation, and ameliorating the Th17-induced microenvironment, indicating the promising potential therapeutic role of ExoMSC in liver fibrosis of PSC or Th17-related diseases.

Human Placental Mesenchymal Stem Cells Relieve Primary Sclerosing Cholangitis via Upregulation of TGR5 in Mdr2-/- Mice and Human Intrahepatic Cholangiocyte Organoid Models.

Primary sclerosing cholangitis (PSC) is a biliary disease accompanied by chronic inflammation of the liver and biliary stricture. Mesenchymal stem cells (MSCs) are used to treat liver diseases because of their immune regulation and regeneration-promoting functions. This study was performed to explore the therapeutic potential of human placental MSCs (hP-MSCs) in PSC through the Takeda G protein-coupled receptor 5 (TGR5) receptor pathway. Liver tissues were collected from patients with PSC and healthy donors (n = 4) for RNA sequencing and intrahepatic cholangiocyte organoid construction. hP-MSCs were injected via the tail vein into Mdr2-/-, bile duct ligation (BDL), and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) mouse models or co-cultured with organoids to confirm their therapeutic effect on biliary cholangitis. Changes in bile acid metabolic profile were analyzed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Compared with healthy controls, liver tissues and intrahepatic cholangiocyte organoids from PSC patients were characterized by inflammation and cholestasis, and marked downregulation of bile acid receptor TGR5 expression. hP-MSC treatment apparently reduced the inflammation, cholestasis, and fibrosis in Mdr2-/-, BDL, and DDC model mice. By activating the phosphatidylinositol 3 kinase/extracellular signal-regulated protein kinase pathway, hP-MSC treatment promoted the proliferation of cholangiocytes, and affected the transcription of downstream nuclear factor κB through regulation of the binding of TGR5 and Pellino3, thereby affecting the cholangiocyte inflammatory phenotype.

Mesenchymal stem cells shift the pro-inflammatory phenotype of neutrophils to ameliorate acute lung injury.

BACKGROUND: Mesenchymal stem cell (MSC) treatment plays a major role in the management of acute lung injury (ALI), and neutrophils are the initial line of defense against ALI. However, the effect of MSCs on neutrophils in ALI remains mostly unknown. METHODS: We investigated the characteristics of neutrophils in lung tissue of ALI mice induced by lipopolysaccharide after treatment with MSCs using single-cell RNA sequencing. Neutrophils separated from lung tissue in ALI were co-cultured with MSCs, and then samples were collected for reverse transcription-polymerase chain reaction and flow cytometry. RESULTS: During inflammation, six clusters of neutrophils were identified, annotated as activated, aged, and circulatory neutrophils. Activated neutrophils had higher chemotaxis, reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase scores than aged neutrophils. Circulatory neutrophils occurred mainly in healthy tissue and were characterized by higher expression of Cxcr2 and Sell. Activated neutrophils tended to exhibit higher expression of Cxcl10 and Cd47, and lower expression of Cd24a, while aged neutrophils expressed a lower level of Cd47 and higher level of Cd24a. MSC treatment shifted activated neutrophils toward an aged neutrophil phenotype by upregulating the expression of CD24, thereby inhibiting inflammation by reducing chemotaxis, ROS production, and NADPH oxidase. CONCLUSION: We identified the immunosuppressive effects of MSCs on the subtype distribution of neutrophils and provided new insight into the therapeutic mechanism of MSC treatment in ALI.

Co-delivery of azithromycin and ibuprofen by ROS-responsive polymer nanoparticles synergistically attenuates the acute lung injury.

Bacterial infection causes lung inflammation and recruitment of several inflammatory factors that may result in acute lung injury (ALI). During bacterial infection, reactive oxygen species (ROS) and other signaling pathways are activated, which intensify inflammation and increase ALI-related mortality and morbidity. To improve the ALI therapy outcome, it is imperative clinically to manage bacterial infection and excessive inflammation simultaneously. Herein, a synergistic nanoplatform (AZI+IBF@NPs) constituted of ROS-responsive polymers (PFTU), and antibiotic (azithromycin, AZI) and anti-inflammatory drug (ibuprofen, IBF) was developed to enable an antioxidative effect, eliminate bacteria, and modulate the inflammatory milieu in ALI. The ROS-responsive NPs (PFTU NPs) loaded with dual-drugs (AZI and IBF) scavenged excessive ROS efficiently both in vitro and in vivo. The AZI+IBF@NPs eradicated Pseudomonas aeruginosa (PA) bacterial strain successfully. To imitate the entry of bacterial-derived compounds in body, a lipopolysaccharide (LPS) model was adopted. The administration of AZI+IBF@NPs via the tail veins dramatically reduced the number of neutrophils, significantly reduced cell apoptosis and total protein concentration in vivo. Furthermore, nucleotide oligomerization domain-like receptor thermal protein domain associated protein 3 (NLRP3) and Interleukin-1 beta (IL-1ß) expressions were most effectively inhibited by the AZI+IBF@NPs. These findings present a novel nanoplatform for the effective treatment of ALI.

[Temporal and Spatial Distribution of Phosphorus in Paddy Fields Under Cyclic Irrigation of Drainage Water].

Considering the potential of cyclic irrigation to increase rainfall use efficiency and reduce agricultural non-point pollution, the experiment of phosphorus transport in paddy fields under cyclic irrigation of drainage water was conducted to address the problem of phosphorus loss pollution and the mismatch between rainfall temporal distribution and crop requirement in the south of China. Lotus pond water and fishpond water were used to irrigate paddy fields for monitoring concentrations of total phosphorus (TP), dissolved phosphorus (DP), and dissolved reactive phosphorus (DRP) in surface water and leachate, and soil profile total phosphorus and Olsen-P concentrations. The results showed that the concentrations of TP, DP and DRP in surface water and leachate decreased along the field under cyclic irrigation of drainage water, especially the phosphorus concentrations of leachate dropped more obviously. As the phosphorus content of cyclic irrigation water sources varied within a certain range, phosphorus concentrations of surface water and leachate did not increased. The concentrations of TP, DP and DRP in surface water and leachate varied with cyclic irrigation time, and the least phosphorus concentrations were observed in August. Top soil Olsen-P concentration decreased along the field and increased with phosphorus content of cyclic irrigation water sources, and soil profile TP concentration was not influenced by cyclic irrigation. Phosphorus removal ratio of paddy field could be increased by extending field length or cyclic irrigation in August.