Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura 35516, Egypt.
Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
Cells. 2023 Jun 1;12(11):1526. doi: 10.3390/cells12111526.
Doxorubicin (DOX) is widely used to treat a variety of malignancies in both adults and children, including those of the bladder, breast, stomach, and ovaries. Despite this, it has been reported to cause hepatotoxicity. The recent discovery of bone marrow-derived mesenchymal stem cells' (BMSCs) therapeutic effects in the context of liver diseases suggests that their administration plays a part in the mitigation and rehabilitation of drug-induced toxicities.
This study investigated whether bone BMSCs could reduce DOX-induced liver damage by blocking the Wnt/β-catenin pathway that causes fibrotic liver.
BMSCs were isolated and treated with hyaluronic acid (HA) for 14 days before injection. Thirty-five mature male SD rats were categorized into four groups; group one (control) rats were supplemented with saline 0.9% for 28 days, group two (DOX) rats were injected with DOX (20 mg/kg), group three (DOX + BMSCs) rats were injected with 2 × 10 BMSCs after 4 days of DOX injection, group four (DOX + BMSCs + HA) rats were injected with 0.1 mL BMSCs pretreated with HA after 4 days of DOX. After 28 days the rats were sacrificed, and blood and liver tissue samples were subjected to biochemical and molecular analysis. Morphological and immunohistochemical observations were also carried out.
In terms of liver function and antioxidant findings, cells treated with HA showed considerable improvement compared to the DOX group ( < 0.05). Moreover, the expression of inflammatory markers (TGFβ1, iNos), apoptotic markers (Bax, Bcl2), cell tracking markers (SDF1α), fibrotic markers (β-catenin, Wnt7b, FN1, VEGF, and Col-1), and ROS markers (Nrf2, HO-1) was improved in BMSCs conditioned with HA in contrast to BMSCs alone ( < 0.05).
Our findings proved that BMSCs treated with HA exert their paracrine therapeutic effects via their secretome, suggesting that cell-based regenerative therapies conditioned with HA may be a viable alternative to reduce hepatotoxicity.
阿霉素（DOX）广泛用于治疗成人和儿童的各种恶性肿瘤，包括膀胱癌、乳腺癌、胃癌和卵巢癌。尽管如此，它已被报道会引起肝毒性。最近发现骨髓间充质干细胞（BMSCs）在肝脏疾病中的治疗作用表明，它们的给药在减轻和恢复药物引起的毒性方面发挥了作用。
本研究旨在探讨骨髓 BMSCs 是否可以通过阻断导致纤维性肝的 Wnt/β-catenin 途径来减轻 DOX 引起的肝损伤。
BMSCs 被分离出来，并在注射前用透明质酸（HA）处理 14 天。35 只成熟雄性 SD 大鼠分为四组；第一组（对照组）大鼠每天补充生理盐水 0.9%，共 28 天；第二组（DOX 组）大鼠注射 DOX（20mg/kg）；第三组（DOX+BMSCs 组）大鼠在 DOX 注射后第 4 天注射 2×10 BMSCs；第四组（DOX+BMSCs+HA 组）大鼠在 DOX 注射后第 4 天注射预先用 HA 处理的 0.1mL BMSCs。28 天后处死大鼠，采集血液和肝脏组织样本进行生化和分子分析。还进行了形态学和免疫组织化学观察。
在肝功能和抗氧化发现方面，与 DOX 组相比，用 HA 处理的细胞有了相当大的改善（<0.05）。此外，与单独的 BMSCs 相比，HA 处理的 BMSCs 改善了炎症标志物（TGFβ1、iNos）、凋亡标志物（Bax、Bcl2）、细胞追踪标志物（SDF1α）、纤维化标志物（β-catenin、Wnt7b、FN1、VEGF 和 Col-1）和 ROS 标志物（Nrf2、HO-1）的表达（<0.05）。
我们的研究结果证明，HA 处理的 BMSCs 通过其分泌产物发挥旁分泌治疗作用，这表明用 HA 调理的基于细胞的再生疗法可能是减轻肝毒性的一种可行替代方法。
