Lysophosphatidic Acid Induces Migration of Human Lung-Resident Mesenchymal Stem Cells Through the β-Catenin Pathway§

Authors

  • Linda Badri,

    1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
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  • Vibha N. Lama

    Corresponding author
    1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
    • Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, 1500 E Medical Center Drive, 3916 Taubman Center, Ann Arbor, Michigan 48109-0360, USA
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    • Telephone: 734-936-5201; Fax: 734-936-8266


  • Author contributions: L.B.: conception and design, collection and/or assembly of data, data analysis and interpretation, and manuscript writing; V.N.L.: conception and design, data analysis and interpretation, manuscript writing, financial support, and final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS July 10, 2012.

Abstract

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. Stem Cells2012;30:2010–2019

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