Therapeutic potential of exosome derived from hepatocyte growth factor-overexpressing adipose mesenchymal stem cells in TGFβ1-stimulated hepatic stellate cells

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS ACS Applied Bio Materials Pub Date : 2024-02-15 DOI:10.1007/s10616-023-00611-0

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Abstract

Cirrhosis is a familiar end-stage of multiple chronic liver diseases. The gene-modified mesenchymal stem cells (MSCs) have become one of the most promising schemes for the treatment of cirrhosis. MSCs exhibit their therapeutic role mainly by secreting hepatocyte growth factor (HGF). The aim of this research was to probe the anti-fibrosis role of exosomes secreted by HGF modified-mouse adipose MSCs (ADMSCs) on activated hepatic stellate cells (HSCs) and to preliminarily explore the possible mechanism. Firstly, mouse ADMSCs were isolated and identified. Quantitative real-time polymerase chain reaction verified the transfection efficiency of ADMSC transfected with HGF lentivirus. Exosomes derived from ADMSC transfecting negative control/HGF (ADMSC^NC-Exo/ADMSC^HGF-Exo) were extracted by density gradient centrifugation. HSCs were allocated to the control, TGF-β, TGF-β + ADMSC-Exo, TGF-β + ADMSC^NC-Exo, and TGF-β + ADMSC^HGF-Exo groups. Moreover, all mice were distributed to the control, CCl₄ (40% CCl₄ in olive oil), CCl₄+ADMSC-Exo, CCl₄+ADMSC^NC-Exo, and CCl₄+ADMSC^HGF-Exo groups. Exosomes derived from ADMSCs with or without HGF transfection suppressed HSC activation, as evidenced by attenuating cell viability and cell cycle arrest at S phase but inducing apoptosis. Moreover, ADMSC-Exo, ADMSC^NC-Exo, and ADMSC^HGF-Exo effectively repressed the gene and protein levels of α-SMA, Col-I, Rho A, Cdc42, and Rac1 in TGF-β-treated HSCs, and ADMSC^HGF-Exo had the best effect. ADMSC^HGF-Exo had a stronger regulatory effect on serum liver index than ADMSC^NC-Exo in CCl₄-induced mice. In conclusion, ADMSC^HGF-Exo alleviated liver fibrosis by weakening the Rho pathway, thus reducing collagen production.

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肝细胞生长因子过表达脂肪间充质干细胞衍生的外泌体对 TGFβ1 刺激的肝星状细胞的治疗潜力

摘要肝硬化是人们熟知的多种慢性肝病的终末阶段。基因修饰间充质干细胞（MSCs）已成为治疗肝硬化最有前景的方案之一。间充质干细胞主要通过分泌肝细胞生长因子（HGF）发挥治疗作用。本研究旨在探究HGF修饰的小鼠脂肪间充质干细胞（ADMSCs）分泌的外泌体对活化的肝星状细胞（HSCs）的抗纤维化作用，并初步探讨其可能的机制。首先，对小鼠 ADMSCs 进行了分离和鉴定。定量实时聚合酶链反应验证了转染 HGF 慢病毒的 ADMSC 的转染效率。通过密度梯度离心提取转染阴性对照/HGF的ADMSC的外泌体（ADMSCNC-Exo/ADMSCHGF-Exo）。造血干细胞被分配到对照组、TGF-β 组、TGF-β + ADMSC-Exo 组、TGF-β + ADMSCNC-Exo 组和 TGF-β + ADMSCHGF-Exo 组。此外，所有小鼠均被分配到对照组、CCl4 组（40% CCl4 溶于橄榄油中）、CCl4+ADMSC-Exo 组、CCl4+ADMSCNC-Exo 组和 CCl4+ADMSCHGF-Exo 组。无论是否转染 HGF，从 ADMSCs 提取的外泌体都能抑制造血干细胞的活化，具体表现为减弱细胞活力和细胞周期停滞在 S 期，但诱导细胞凋亡。此外，ADMSC-Exo、ADMSCNC-Exo和ADMSCHGF-Exo能有效抑制TGF-β处理的造血干细胞中α-SMA、Col-I、Rho A、Cdc42和Rac1的基因和蛋白水平，其中ADMSCHGF-Exo的效果最好。与 ADMSCNC-Exo 相比，ADMSCHGF-Exo 对 CCl4 诱导的小鼠血清肝指数有更强的调节作用。总之，ADMSCHGF-Exo可通过削弱Rho通路缓解肝纤维化，从而减少胶原蛋白的产生。

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