Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan 48109-0360, USA.
Stem Cells. 2012 Sep;30(9):2010-9. doi: 10.1002/stem.1171.
Mesenchymal stem cells (MSCs) have been demonstrated to reside in human adult organs. However, mechanisms of migration of these endogenous MSCs within their tissue of origin are not well understood. Here, we investigate migration of human adult lung-resident (LR) mesenchymal progenitor cells. We demonstrate that bioactive lipid lysophosphatidic acid (LPA) plays a principal role in the migration of human LR-MSCs through a signaling pathway involving LPA1-induced β-catenin activation. LR-MSCs isolated from human lung allografts and lungs of patients with scleroderma demonstrated a robust migratory response to LPA in vitro. Furthermore, LPA levels correlated with LR-MSC numbers in bronchoalveolar lavage (BAL), providing demonstration of the in vivo activity of LPA in human adult lungs. Migration of LR-MSCs was mediated via LPA1 receptor ligation and LPA1 silencing significantly abrogated the migratory response of LR-MSCs to LPA as well as human BAL. LPA treatment of LR-MSCs induced protein kinase C-mediated glycogen synthase kinase-3β phosphorylation, with resulting cytoplasmic accumulation and nuclear translocation of β-catenin. TCF/LEF dual luciferase gene reporter assay demonstrated a significant increase in transcriptional activity after LPA treatment. LR-MSC migration and increase in reporter gene activity in the presence of LPA were abolished by transfection with β-catenin small interfering RNA demonstrating that β-catenin is critical in mediating LPA-induced LR-MSC migration. These data delineate a novel signaling pathway through which ligation of a G protein-coupled receptor by a biologically relevant lipid mediator induces migration of human tissue-resident mesenchymal progenitors.
间质干细胞（MSCs）已被证实存在于成人器官中。然而，这些内源性 MSCs 在其组织起源中的迁移机制尚不清楚。在这里，我们研究了人成年肺驻留（LR）间充质祖细胞的迁移。我们证明生物活性脂质溶血磷脂酸（LPA）通过涉及 LPA1 诱导的β-连环蛋白激活的信号通路在人 LR-MSCs 的迁移中起主要作用。从人肺同种异体移植物和硬皮病患者的肺中分离的 LR-MSCs 在体外对 LPA 表现出强烈的迁移反应。此外，LPA 水平与支气管肺泡灌洗液（BAL）中的 LR-MSC 数量相关，证明了 LPA 在人成年肺中的体内活性。LR-MSCs 的迁移是通过 LPA1 受体的结合介导的，LPA1 沉默显著阻断了 LR-MSCs 对 LPA 以及人 BAL 的迁移反应。LPA 处理 LR-MSCs 诱导蛋白激酶 C 介导的糖原合酶激酶-3β磷酸化，导致β-连环蛋白的细胞质积累和核转位。TCF/LEF 双荧光素酶基因报告基因测定表明，LPA 处理后转录活性显著增加。LR-MSC 迁移和在 LPA 存在下报告基因活性的增加在转染β-连环蛋白小干扰 RNA 后被废除，证明β-连环蛋白在介导 LPA 诱导的 LR-MSC 迁移中是至关重要的。这些数据描绘了一条新的信号通路，通过该通路，生物相关脂质介质与 G 蛋白偶联受体的结合诱导人组织驻留间充质祖细胞的迁移。
