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

Abstract

Mesenchymal stem cells (MSC) 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 mesenchymal progenitor cells. We demonstrate that bioactive lipid lysophosphatidic acid (LPA) plays a principal role in the migration of human lung-resident mesenchymal stem cells (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 PKC-mediated glycogen synthase kinase-3β (GSK3β) 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 was abolished by transfection with β-catenin siRNA 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.

In vitro evaluation of lysophosphatidic acid delivery via reverse perfluorocarbon emulsions to enhance alveolar epithelial repair

“…However, it has been shown for other cell types including fibroblasts and mesenchymal stem cells [38–40]. For alveolar epithelial cells, we see a dose-dependent increase in proliferation with aqueous LPA.…”

Targeting the Myofibroblast Genetic Switch: Inhibitors of Myocardin-Related Transcription Factor/Serum Response Factor–Regulated Gene Transcription Prevent Fibrosis in a Murine Model of Skin Injury

“…Autocrine secretion of LPA and overexpression of mitogenic cytokines such as CTGF contributes to cell proliferation in fibrotic tissues (Badri and Lama, 2012;Sakai et al, 2013). SSc cells proliferated faster than normal dermal fibroblasts in vitro, and this increase in growth was selectively blocked by CCG-203971 (Fig.…”

Therapeutic Potential of Mesenchymal Stem Cells in Regenerative Medicine

“…Moreover, in regenerating skeletal tissues, the MSCs homing may be improved with growth factor delivery, as combined MSCs and erythropoietin infusion gave better results in limb ischemia treatment [45]. Bioactive lipid lysophosphatidic acid (LPA) plays a principal role in the migration of human lung resident MSCs through a signaling pathway involving LPA1-induced beta-catenin activation [46]. Anti-inflammatory environment is more accommodating to the therapeutic hMSCs than a proinflammatory environment [47].…”