Charoenphannathon Jennie S, Wong Pui D, Royce Simon G, Jaffar Jade, Westall Glen P, Wang Chao, Bourke Jane E, Samuel Chrishan S
Cardiovascular Disease Program, Monash Biomedicine Discovery Institute and Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
Alfred Health, Melbourne, Victoria, Australia.
Biomed Pharmacother. 2025 Sep;190:118370. doi: 10.1016/j.biopha.2025.118370. Epub 2025 Jul 21.
Idiopathic pulmonary fibrosis (IPF) is a fatal condition associated with excessive interstitial collagen accumulation and irreversible lung function decline, for which there is no effective cure. Hence, this study evaluated the dose-dependent anti-fibrotic effects of bone marrow mesenchymal stem cell-derived extracellular vesicles (BM-MSC-EVs) in transforming growth factor (TGF)-β1-stimulated human dermal myofibroblasts (1 ×10-1 ×10 BM-MSC-EVs) and TGF-β1-stimulated lung myofibroblasts isolated from non-IPF versus and IPF patients (1 ×10-1 ×10 BM-MSC-EVs) after 72 h in culture; and when intranasally-administered therapeutically (from days 21-28 post-injury) to bleomycin (BLM)-injured mice (2.5 ×10-2.5 ×10 BM-MSC-EVs). In each case, changes in myofibroblast differentiation, collagen I deposition, matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 levels, and MMP-2:TIMP-2 and MMP-9:TIMP-1 ratios were assessed. BM-MSC-EVs significantly attenuated human dermal and non-IPF patient-derived lung myofibroblast differentiation and collagen I deposition in an inverse dose-dependent manner after 72 h, with the lowest doses evaluated inducing the strongest inhibitory effects. Similarly, BM-MSC-EVs therapeutically reduced the BLM-induced lung TGF-β1 expression and signal transduction, myofibroblast differentiation and collagen I deposition, and restored the BLM-induced loss of dynamic lung compliance in an inverse dose-dependent manner in vivo, after 7-days of treatment. BM-MSC-EVs promoted the MMP-2:TIMP-2 ratio in human dermal myofibroblasts or the MMP-9:TIMP-1 ratio in human lung myofibroblasts and the murine lung as part of their anti-fibrotic effects. Notably, BM-MSC-EVs failed to exert any anti-fibrotic effects in TGF-β1-stimulated lung myofibroblasts isolated from IPF patients. These findings suggested that BM-MSC-EVs may provide an anti-fibrotic treatment option for early-to-moderate IPF, but may not be effective against advanced IPF.
特发性肺纤维化（IPF）是一种致命疾病，与过多的间质胶原积累和不可逆的肺功能下降相关，目前尚无有效治愈方法。因此，本研究评估了骨髓间充质干细胞衍生的细胞外囊泡（BM-MSC-EVs）在转化生长因子（TGF）-β1刺激的人皮肤成肌纤维细胞（1×10 - 1×10 BM-MSC-EVs）以及从非IPF患者和IPF患者分离的TGF-β1刺激的肺成肌纤维细胞（1×10 - 1×10 BM-MSC-EVs）培养72小时后的剂量依赖性抗纤维化作用；以及在对博来霉素（BLM）损伤的小鼠进行治疗性鼻内给药（损伤后第21 - 28天）时（2.5×10 - 2.5×10 BM-MSC-EVs）的作用。在每种情况下，评估成肌纤维细胞分化、I型胶原沉积、基质金属蛋白酶（MMP）-2、MMP-9、金属蛋白酶组织抑制剂（TIMP）-1和TIMP-2水平的变化，以及MMP-2:TIMP-2和MMP-9:TIMP-1比值。72小时后，BM-MSC-EVs以剂量依赖性方式显著减弱人皮肤和非IPF患者来源的肺成肌纤维细胞分化及I型胶原沉积，所评估的最低剂量诱导最强抑制作用。同样，治疗性给予BM-MSC-EVs可在体内治疗7天后以剂量依赖性方式降低BLM诱导的肺TGF-β1表达和信号转导、成肌纤维细胞分化及I型胶原沉积，并恢复BLM诱导的动态肺顺应性丧失。作为其抗纤维化作用的一部分，BM-MSC-EVs促进人皮肤成肌纤维细胞中的MMP-2:TIMP-2比值或人肺成肌纤维细胞及小鼠肺中的MMP-9:TIMP-1比值。值得注意的是，BM-MSC-EVs对从IPF患者分离的TGF-β1刺激的肺成肌纤维细胞未发挥任何抗纤维化作用。这些发现表明，BM-MSC-EVs可能为早期至中度IPF提供一种抗纤维化治疗选择，但对晚期IPF可能无效。
