Mincheva Gergana, Moreno-Manzano Victoria, Felipo Vicente, Llansola Marta
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Laboratory of Neuronal and Tissue Regeneration, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Life Sci. 2025 Mar 1;364:123429. doi: 10.1016/j.lfs.2025.123429. Epub 2025 Jan 28.
Preventing the progression of liver damage to fibrosis would be beneficial for patients with steatotic liver disease (SLD). Mesenchymal stem cells (MSC) are a promising therapy for SLD and derived extracellular vesicles (EVs) could even improve the treatment's efficacy and safety. However, the mechanisms of MSC-EVs beneficial effects are not well known. It has been suggested that modifying the EVs cargo could improve their beneficial effects. The aims of this study were to assess if MSC-EVs reduce liver damage in a rat model of mild liver damage; to analyze the underlying mechanisms and to assess if silencing TGFβ enhances the beneficial effects of MSC-EVs. CCl was injected three times per week during four weeks to induce mild liver damage. EVs from human adipocyte MSC and from TGFβ-depleted MSC (siTGFβ-MSC-EVs) were injected in the tail vein. Steatosis, fibrosis, liver inflammation, macrophage infiltration and liver content of fibrotic markers, DAMPs, cytokines and bile acids were analyzed. Normal MSC-EVs reduce the CCL2 increase in liver, macrophage infiltration and the increases in the fibrosis markers collagen I and α-SMA. Treatment with siTGFβ-MSC-EVs, in addition, reduces liver steatosis, the increase of bile acids (mainly TCA), and DAMP HMGB1 levels, inducing a larger reduction of collagen I in liver of CCl rats. Treatment with MSCs-EVs effectively reduces early liver damage. Silencing of TGFβ in MSCs enhances the beneficial effects by additional mechanisms. Early treatment with MSC-EVs, especially after silencing TGFβ, could improve liver damage in SLD patients.
预防肝损伤进展为肝纤维化对脂肪性肝病（SLD）患者有益。间充质干细胞（MSC）是治疗SLD的一种有前景的疗法，其衍生的细胞外囊泡（EVs）甚至可以提高治疗的疗效和安全性。然而，MSC-EVs有益作用的机制尚不清楚。有人提出，修饰EVs的货物可以改善其有益作用。本研究的目的是评估MSC-EVs是否能减轻轻度肝损伤大鼠模型中的肝损伤；分析其潜在机制，并评估沉默转化生长因子β（TGFβ）是否能增强MSC-EVs的有益作用。在四周内每周三次注射四氯化碳（CCl）以诱导轻度肝损伤。将来自人脂肪间充质干细胞的EVs和来自TGFβ缺失的间充质干细胞的EVs（siTGFβ-MSC-EVs）注入尾静脉。分析了脂肪变性、纤维化、肝脏炎症、巨噬细胞浸润以及纤维化标志物、损伤相关分子模式（DAMPs）、细胞因子和胆汁酸的肝脏含量。正常的MSC-EVs可降低肝脏中CCL2的增加、巨噬细胞浸润以及纤维化标志物I型胶原蛋白和α-平滑肌肌动蛋白（α-SMA）的增加。此外，用siTGFβ-MSC-EVs治疗可减少肝脏脂肪变性、胆汁酸（主要是三氯乙酸）的增加以及DAMP高迁移率族蛋白B1（HMGB1）水平，从而使CCl大鼠肝脏中的I型胶原蛋白减少得更多。用MSC-EVs治疗可有效减轻早期肝损伤。间充质干细胞中TGFβ的沉默通过其他机制增强了有益作用。早期用MSC-EVs治疗，尤其是在沉默TGFβ后，可能改善SLD患者的肝损伤。
