Dux4 controls migration of mesenchymal stem cells through the Cxcr4-Sdf1 axis

// Petr Dmitriev 1, 2, * , Ekaterina Kiseleva 2, 3, * , Olga Kharchenko 2, 3 , Evgeny Ivashkin 2, 3 , Andrei Pichugin 2, 3, 7 , Philippe Dessen 4 , Thomas Robert 4 , Frederique Coppee 5 , Alexandra Belayew 5 , Gilles Carnac 6 , Dalila Laoudj-Chenivesse 6 , Marc Lipinski 1, 2 , Andrei Vasiliev 3 , Yegor S. Vassetzky 1, 2, 3 1 UMR 8126, Univ. Paris-Sud, CNRS, Institut de Cancerologie Gustave-Roussy, Villejuif, France 2 LIA1066 Laboratoire Franco-Russe de Recherches en Oncologie, Villejuif, France 3 N.K. Koltzov Institute of Developmental Biology, RAS, Moscow, Russia 4 Functional Genomics Unit, Institut de Cancerologie Gustave-Roussy, Villejuif, France 5 Laboratory of Molecular Biology, Research Institute for Health Sciences and Technology, University of Mons, Mons, Belgium 6 PhyMedExp, University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France 7 Peter the Great St. Petersburg Polytechnic University, St. Petersburg, Russia * These authors contributed equally to this work Correspondence to: Yegor S. Vassetzky, email: vassetzky@igr.fr Keywords: DUX4, CXCR4, SDF1, signalling, migration Received: April 01, 2016      Accepted: August 10, 2016      Published: August 18, 2016 ABSTRACT We performed transcriptome profiling of human immortalized myoblasts (MB) transiently expressing double homeobox transcription factor 4 (DUX4) and double homeobox transcription factor 4 centromeric (DUX4c) and identified 114 and 70 genes differentially expressed in DUX4- and DUX4c- transfected myoblasts, respectively. A significant number of differentially expressed genes were involved in inflammation, cellular migration and chemotaxis suggesting a role for DUX4 and DUX4c in these processes. DUX4 but not DUX4c overexpression resulted in upregulation of the CXCR4 (C-X-C motif Receptor 4) and CXCL12 (C-X-C motif ligand 12 also known as SDF1) expression in human immortalized myoblasts. In a Transwell cell migration assay, human bone marrow-derived mesenchymal stem cells (BMSCs) were migrating more efficiently towards human immortalized myoblasts overexpressing DUX4 as compared to controls; the migration efficiency of DUX4-transfected BMSCs was also increased. DUX4c overexpression in myoblasts or in BMSCs had no impact on the rate of BMSC migration. Antibodies against SDF1 and CXCR4 blocked the positive effect of DUX4 overexpression on BMSC migration. We propose that DUX4 controls the cellular migration of mesenchymal stem cells through the CXCR4 receptor.