Peking University Stem Cell Research Center, Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
J Cell Mol Med. 2014 Jan;18(1):156-69. doi: 10.1111/jcmm.12178. Epub 2013 Nov 19.
Lung fibrosis is characterized by vascular leakage and myofibroblast recruitment, and both phenomena are mediated by lysophosphatidic acid (LPA) via its type-1 receptor (LPA1). Following lung damage, the accumulated myofibroblasts activate and secrete excessive extracellular matrix (ECM), and form fibrotic foci. Studies have shown that bone marrow-derived cells are an important source of myofibroblasts in the fibrotic organ. However, the type of cells in the bone marrow contributing predominantly to the myofibroblasts and the involvement of LPA-LPA1 signalling in this is yet unclear. Using a bleomycin-induced mouse lung-fibrosis model with an enhanced green fluorescent protein (EGFP) transgenic mouse bone marrow replacement, we first demonstrated that bone marrow derived-mesenchymal stem cells (BMSCs) migrated markedly to the bleomycin-injured lung. The migrated BMSC contributed significantly to α-smooth muscle actin (α-SMA)-positive myofibroblasts. By transplantation of GFP-labelled human BMSC (hBMSC) or EGFP transgenic mouse BMSC (mBMSC), we further showed that BMSC might be involved in lung fibrosis in severe combined immune deficiency (SCID)/Beige mice induced by bleomycin. In addition, using quantitative-RT-PCR, western blot, Sircol collagen assay and migration assay, we determined the underlying mechanism was LPA-induced BMSC differentiation into myofibroblast and the secretion of ECM via LPA1. By employing a novel LPA1 antagonist, Antalpa1, we then showed that Antalpa1 could attenuate lung fibrosis by inhibiting both BMSC differentiation into myofibroblast and the secretion of ECM. Collectively, the above findings not only further validate LPA1 as a drug target in the treatment of pulmonary fibrosis but also elucidate a novel pathway in which BMSCs contribute to the pathologic process.
肺纤维化的特征是血管渗漏和肌成纤维细胞募集，这两种现象都是通过溶血磷脂酸（LPA）与其 1 型受体（LPA1）介导的。在肺损伤后，积累的肌成纤维细胞激活并分泌过多的细胞外基质（ECM），形成纤维性病灶。研究表明，骨髓来源的细胞是纤维化器官中肌成纤维细胞的重要来源。然而，骨髓中哪种类型的细胞主要贡献于肌成纤维细胞，以及 LPA-LPA1 信号通路在此过程中的参与情况尚不清楚。我们使用增强型绿色荧光蛋白（EGFP）转基因小鼠骨髓替代的博来霉素诱导的小鼠肺纤维化模型，首次证明骨髓来源的间充质干细胞（BMSC）明显迁移到博来霉素损伤的肺。迁移的 BMSC 显著促进α-平滑肌肌动蛋白（α-SMA）阳性肌成纤维细胞的形成。通过移植 GFP 标记的人 BMSC（hBMSC）或 EGFP 转基因小鼠 BMSC（mBMSC），我们进一步表明，BMSC 可能参与了博来霉素诱导的严重联合免疫缺陷（SCID）/Beige 小鼠的肺纤维化。此外，通过定量 RT-PCR、Western blot、Sircol 胶原测定和迁移测定，我们确定潜在的机制是 LPA 通过 LPA1 诱导 BMSC 分化为肌成纤维细胞和 ECM 的分泌。通过使用新型 LPA1 拮抗剂 Antalpa1，我们随后表明 Antalpa1 可以通过抑制 BMSC 分化为肌成纤维细胞和 ECM 的分泌来减轻肺纤维化。总之，这些发现不仅进一步验证了 LPA1 作为治疗肺纤维化的药物靶点的作用，还阐明了 BMSC 参与病理过程的新途径。
