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PDGFRβ-targeted TRAIL specifically induces apoptosis of activated hepatic stellate cells and ameliorates liver fibrosis

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Abstract

Liver fibrosis usually progresses to liver cirrhosis and even hepatocellular carcinoma. Since activated hepatic stellate cells (aHSCs) are responsible for liver fibrosis, reducing the quantity of aHSCs was considered the essential strategy for clinical antihepatofibrotic therapy. Due to the overexpression of TRAIL receptor 2 (DR5) in aHSCs, human TNF-related apoptosis-inducing ligand (hTRAIL) that could induce aHSCs apoptosis might be feasible for antihepatofibrotic therapy. However, the in vivo aHSCs-apoptosis-induction of hTRAIL is limited by its poor cell-targeting and a short half-life. In this study, we found that platelet-derived growth factor receptor β (PDGFRβ) was co-expressed with DR5 in aHSCs. And the ZPDGFRβ affibody with high affinity for PDGFRβ could bind aHSCs and, thus, accumulate in the fibrotic liver. ZPDGFRβ was fused to hTRAIL to produce the fusion protein Z-hTRAIL. Compared to hTRAIL, Z-hTRAIL showed greater in vitro cell binding and apoptosis-induction in aHSCs. In addition, Z-hTRAIL induced apoptosis of aHSCs but spared other normal liver cells. In vivo, Z-hTRAIL accumulated preferentially in fibrotic livers and exerted greater effects than hTRAIL in inducing aHSCs apoptosis and reducing extracellular matrix (ECM) deposition. These results demonstrated that the antihepatofibrotic effect of hTRAIL was improved by PDGFRβ-targeted delivery. To enhance its pharmacokinetics, Z-hTRAIL was modified with 10 kDa polyethylene glycol (PEG), which significantly (30–40 times) prolonged its half-life. The PEGylated long-acting Z-hTRAIL was more potent than the native Z-hTRAIL in regressing liver fibrosis. These results suggest that the aHSC-targeting and long-acting Z-hTRAIL might serve as a novel tool for antihepatofibrotic therapy.

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Acknowledgements

This study was funded by the National Natural Science Fund of China (81273419, 81573336, LXF) and “1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University” (ZYGD18014, CJQ).

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  1. Rui Li and Zhao Li contributed equally to this work.

Authors and Affiliations

  1. Key Lab of Transplant Engineering and Immunology, MOH; Regenerative Medical Research Center, West China Hospital, Sichuan University, Chengdu, 610041, China

    Rui Li, Zhao Li, Yanru Feng, Hao Yang, Qiuxiao Shi, Ze Tao, Jingqiu Cheng & Xiaofeng Lu

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  1. Rui Li
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Li, R., Li, Z., Feng, Y. et al. PDGFRβ-targeted TRAIL specifically induces apoptosis of activated hepatic stellate cells and ameliorates liver fibrosis. Apoptosis 25, 105–119 (2020). https://doi.org/10.1007/s10495-019-01583-3

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