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Chemically modified liposomes carrying TRAIL target activated hepatic stellate cells and ameliorate hepatic fibrosis in vitro and in vivo.

ABSTRACT: At present, no satisfactory anti-liver fibrosis drugs have been used clinically due to the poor targeting ability and short half-life period. This study aimed to explore the effects of a new TRAIL (TNF-related apoptosis-inducing ligand) preparation that can target aHSCs (activated hepatic stellate cells) on liver fibrosis and explain the possible underlying mechanism. Using our self-made drug carrier pPB-SSL that specifically targets aHSCs, recombinant human TRAIL (rhTRAIL) protein was embedded in (named as pPB-SSL-TRAIL) and applied to treat liver fibrotic mice as well as 3T3 fibroblast cells and aHSCs. Through in vitro and in vivo experiments, we found that, compared with the groups treated with TRAIL (free rhTRAIL) and SSL-TRAIL (rhTRAIL capsulated within unmodified liposome), the group treated with pPB-SSL-TRAIL nanoparticles showed significantly lower cell viability and higher cell apoptosis in vitro. The targeting delivering system pPB-SSL also significantly enhanced the anti-fibrotic effect, apoptosis induction and long circulation of rhTRAIL. After the treatment with pPB-SSL-TRAIL, apoptosis of aHSCs was notably increased and hepatic fibrosis in mice was remarkably alleviated. In vitro, pPB-SSL-TRAIL nanoparticles were mainly transported and located on membrane or into cytoplasm, but the particles were distributed mainly in mouse fibrotic liver and most on the cell membrane of aHSCs. In conclusion, rhTRAIL carried by pPB-SSL delivering system has prolonged circulation in blood, be able to target aHSCs specifically, and alleviate fibrosis both in vitro and in vivo. It presents promising prospect in the therapy of liver fibrosis, and it is worthwhile for us to develop it for clinical use.

SUBMITTER: Li Q

PROVIDER: S-EPMC6378220 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Chemically modified liposomes carrying TRAIL target activated hepatic stellate cells and ameliorate hepatic fibrosis in vitro and in vivo.

Li Qinghua Q Ding Youcheng Y Guo Xinlai X Luo Shenggen S Zhuang Huiren H Zhou JingE J Xu Nan N Yan Zhiqiang Z

Journal of cellular and molecular medicine 20181227 3

At present, no satisfactory anti-liver fibrosis drugs have been used clinically due to the poor targeting ability and short half-life period. This study aimed to explore the effects of a new TRAIL (TNF-related apoptosis-inducing ligand) preparation that can target aHSCs (activated hepatic stellate cells) on liver fibrosis and explain the possible underlying mechanism. Using our self-made drug carrier pPB-SSL that specifically targets aHSCs, recombinant human TRAIL (rhTRAIL) protein was embedded ...[more]

PMID: 30592139

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Project description:BackgroundLiver fibrosis (LF) is a common pathological process characterized by the activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix. Severe LF causes cirrhosis and even liver failure, a major cause of morbidity and mortality worldwide. Transplantation of human placental mesenchymal stem cells (hPMSCs) has been considered as an alternative therapy. However, the underlying mechanisms and the appropriate time window for hPMSC transplantation are not well understood.MethodsWe established mouse models of CCl4-injured LF and administered hPMSCs at different stages of LF once a week for 2 weeks. The therapeutic effect of hPMSCs on LF was investigated, according to histopathological and blood biochemical analyses. In vitro, the effect of hPMSCs and the secretomes of hPMSCs on the inhibition of activated HSCs was assessed. RNA sequencing (RNA-seq) analysis, real-time PCR array, and western blot were performed to explore possible signaling pathways involved in treatment of LF with hPMSCs.ResultshPMSC treatment notably alleviates experimental hepatic fibrosis, restores liver function, and inhibits inflammation. Furthermore, the therapeutic effect of hPMSCs against mild-to-moderate LF was significantly greater than against severe LF. In vitro, we observed that the hPMSCs as well as the secretomes of hPMSCs were able to decrease the activation of HSCs. Mechanistic dissection studies showed that hPMSC treatment downregulated the expression of fibrosis-related genes, and this was accompanied by the upregulation of Caveolin-1 (Cav1) (p < 0.001). This suggested that the amelioration of LF occurred partly due to the restoration of Cav1 expression in activated HSCs. Upregulation of Cav1 can inhibit the TGF-β/Smad signaling pathway, mainly by reducing Smad2 phosphorylation, resulting in the inhibition of activated HSCs, whereas this effect could be abated if Cav1 was silenced in advance by siRNAs.ConclusionsOur findings suggest that hPMSCs could provide multifaceted therapeutic benefits for the treatment of LF, and the TGF-β/Cav1 pathway might act as a therapeutic target for hPMSCs in the treatment of LF.

Dataset Information

Chemically modified liposomes carrying TRAIL target activated hepatic stellate cells and ameliorate hepatic fibrosis in vitro and in vivo.

Publications

Chemically modified liposomes carrying TRAIL target activated hepatic stellate cells and ameliorate hepatic fibrosis in vitro and in vivo.

Similar Datasets

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