Exosomes derived from diabetic microenvironment-preconditioned mesenchymal stem cells ameliorate nonalcoholic fatty liver disease and inhibit pyroptosis of hepatocytes

Article

Author: Zhao, Jian ; Su, Wanlu ; Zhang, HaiXia ; Li, Bing ; Mu, Yiming ; Lyu, Zhaohui ; Zhang, Yue ; Ren, Rui ; Wang, Anning ; Cheng, Yu ; Hu, Ruofan

AIMPyroptosis, a type of programmed cell death, is a key mechanism underlying non-alcoholic fatty liver disease (NAFLD). Mesenchymal stem cell (MSC)-derived exosomes (MSC-Exos) have the potential to ameliorate NAFLD, an effect that is enhanced by curcumin preconditioning. We previously reported that diabetic microenvironment preconditioning enhances the secretion capacity and anti-inflammatory activity of MSCs. Therefore, we hypothesized that MSC-Exos would inhibit hepatocyte pyroptosis and thereby ameliorate NAFLD, and that diabetic microenvironment preconditioning would enhance these effects.METHODSMSCs were preconditioned in a diabetic microenvironment (pMSCs). MSC-Exos and pMSC-Exos collected from MSCs or pMSCs were applied to methionine- and choline-deficient (MCD)-induced NAFLD mice and in vitro models involving induction with lipopolysaccharide or palmitic acid to mimic hepatic steatosis and injury. MCC950 treatment was used as a positive control. We analyzed the characteristics of NAFLD and pyroptosis markers. Protein profiles of MSC-Exos and pMSC-Exos were evaluated by label-free quantitative proteomics.RESULTSIn vivo, MSC-Exos partially attenuated inflammation and fibrosis, but not lipid deposition and NAFLD progression in the livers of NAFLD mice. pMSC-Exos significantly improved lipid metabolism, hepatic steatosis, inflammation, and fibrosis but also retarded the progression of NAFLD. Pyroptosis was upregulated in the liver of NAFLD mice. MSC-Exos and pMSC-Exos inhibited pyroptosis, and the effect of the latter was greater than that of the former. In vitro, MSC-Exos and pMSC-Exos ameliorated hepatocyte steatosis, lipid metabolism disorder, and inflammation, and pMSC-Exos exerted a greater inhibitory effect on hepatocyte pyroptosis than MSC-Exos did, which were remitted after inhibition of peroxiredoxin-1 (PRDX-1).CONCLUSIONMSC-Exos ameliorated NAFLD and inhibited hepatocyte pyroptosis by downregulating the NLRP3/Caspase-1/GSDMD pathway, effects enhanced by pMSC-Exos, partly due to PRDX-1 upregulation.

01 Dec 2024·International Immunopharmacology

Exosomes derived from primary cartilage stem/progenitor cells promote the repair of osteoarthritic chondrocytes by modulating immune responses

Article

Author: Yang, Hongwei ; Han, Yangyun ; Chen, Zhifeng ; Chen, Jing ; Yang, Jian ; Long, Xiaodong ; Tan, Ya ; Li, Xiaodi

BACKGROUNDExosomes derived from primary chondrogenic stem/progenitor cells (CSPCs-EXOs) show promise in cartilage repair due to their immunomodulatory and regenerative properties. However, their specific therapeutic potential in osteoarthritis (OA), especially in modulating immune responses and enhancing chondrocyte function, requires further exploration. This study aims to clarify CSPCs-EXOs' effects on OA by investigating their role in chondrocyte proliferation, migration, inflammation inhibition, and cartilage regeneration.METHODSA rat model of osteoarthritis was established using monosodium iodoacetate (MIA). CSPCs-EXOs were isolated and characterized before being administered to the OA rats. Comprehensive transcriptomic analysis was conducted to identify differentially expressed genes (DEGs) and signaling pathways influenced by CSPCs-EXOs. Histopathological evaluation of cartilage tissue, immunohistochemistry, and in vitro assays were performed to assess chondrocyte proliferation, migration, inflammation, and intracellular environmental changes.RESULTSCSPCs-EXOs treatment significantly reduced OA-induced cartilage damage, shown by improved histopathological features, increased chondrocyte proliferation, migration, and enhanced cartilage matrix integrity. CSPCs-EXOs uniquely modulated immune pathways and enhanced cellular repair, setting them apart from traditional treatments. Transcriptomic analysis revealed regulation of immune response, inflammation, oxidative stress, and DNA repair pathways. CSPCs-EXOs downregulated inflammatory cytokines (TNF, IL-17) and upregulated pathways for cellular proliferation, migration, and metabolism. They also altered splicing patterns of DNA repair enzymes, indicating a role in boosting repair mechanisms.CONCLUSIONSCSPCs-EXOs promote cartilage repair in osteoarthritis by modulating immune responses, inhibiting inflammation, and improving the intracellular environment. These findings emphasize their innovative therapeutic potential and offer key insights into their regenerative mechanisms, positioning CSPCs-EXOs as a promising strategy for OA treatment and a foundation for future clinical applications in cartilage tissue engineering and regenerative medicine.

01 Dec 2024·Life Sciences

Exosomes from human bone marrow MSCs alleviate PD-1/PD-L1 inhibitor-induced myocardial injury in melanoma mice by regulating macrophage polarization and pyroptosis

Article

Author: Zhang, Mengyu ; Wang, Shuo ; Zhong, Li ; Qin, Qin ; Guo, Rui ; Liu, Xiaoyu ; Fang, Yue ; Zhou, Bingqian

Myocarditis, which can be triggered by immune checkpoint inhibitor (ICI) treatment, represents a critical and severe adverse effect observed in cancer therapy. Thus, elucidating the underlying mechanism and developing effective strategies to mitigate its harmful impact is of utmost importance. The objective of this study is to investigate the potential role and regulatory mechanism of exosomes derived from human bone marrow mesenchymal stem cells (hBMSC-Exos) in providing protection against myocardial injury induced by ICIs. We observed that the administration of programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitor BMS-1 in tumor-bearing mice led to evident cardiac dysfunction and myocardial injury, which were closely associated with M1 macrophage polarization and cardiac pyroptosis. Remarkably, these adverse effects were significantly alleviated through tail-vein injection of hBMSC-Exos. Moreover, either BMS-1 or hBMSC-Exos alone demonstrated the ability to reduce tumor size, while the combination of hBMSC-Exos with BMS-1 treatment not only effectively improved the probability of tumor inhibition but also alleviated cardiac anomalies induced by BMS-1.

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Indication	Highest Phase	Country/Location	Organization	Date
Epilepsies, Partial	Phase 1	CN	Guodian (Beijing) Pharmaceutical Technology Co., Ltd.	23 May 2023

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