title: Gene Expression Profiling of Muscle Stem Cells Identifies Novel Regulators of Postnatal Myogenesis.
abstract: Skeletal muscle growth and regeneration require a population of muscle stem cells, the satellite cells, located in close contact to the myofiber. These cells are specified during fetal and early postnatal development in mice from a Pax3/7 population of embryonic progenitor cells. As little is known about the genetic control of their formation and maintenance, we performed a genome-wide chronological expression profile identifying the dynamic transcriptomic changes involved in establishment of muscle stem cells through life, and acquisition of muscle stem cell properties. We have identified multiple genes and pathways associated with satellite cell formation, including set of genes specifically induced (EphA1, EphA2, EfnA1, EphB1, Zbtb4, Zbtb20) or inhibited (EphA3, EphA4, EphA7, EfnA2, EfnA3, EfnA4, EfnA5, EphB2, EphB3, EphB4, EfnBs, Zfp354c, Zcchc5, Hmga2) in adult stem cells. Ephrin receptors and ephrins ligands have been implicated in cell migration and guidance in many tissues including skeletal muscle. Here we show that Ephrin receptors and ephrins ligands are also involved in regulating the adult myogenic program. Strikingly, impairment of EPHB1 function in satellite cells leads to increased differentiation at the expense of self-renewal in isolated myofiber cultures. In addition, we identified new transcription factors, including several zinc finger proteins. ZFP354C and ZCCHC5 decreased self-renewal capacity when overexpressed, whereas ZBTB4 increased it, and ZBTB20 induced myogenic progression. The architectural and transcriptional regulator HMGA2 was involved in satellite cell activation. Together, our study shows that transcriptome profiling coupled with myofiber culture analysis, provides an efficient system to identify and validate candidate genes implicated in establishment/maintenance of muscle stem cells. Furthermore, tour de force transcriptomic profiling provides a wealth of data to inform for future stem cell-based muscle therapies.
authors.affiliation: Institut Mondor de Recherche Biomédicale, INSERM U955-E10Créteil, France; Université Paris Est, Faculté de MedecineCréteil, France; Ecole Nationale Veterinaire d'AlfortMaison Alfort, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Alonso-Martin
authors.affiliation: Institut Mondor de Recherche Biomédicale, INSERM U955-E10 Créteil, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Rochat
authors.affiliation: Institut Mondor de Recherche Biomédicale, INSERM U955-E10Créteil, France; Université Paris Est, Faculté de MedecineCréteil, France; Ecole Nationale Veterinaire d'AlfortMaison Alfort, France.
authors.forename: Despoina
authors.initials: D
authors.lastname: Mademtzoglou
authors.affiliation: Institut Mondor de Recherche Biomédicale, INSERM U955-E10 Créteil, France.
authors.forename: Jessica
authors.initials: J
authors.lastname: Morais
authors.affiliation: Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer Paris, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reyniès
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, Center for Research in Myology Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Auradé
authors.affiliation: Institut Mondor de Recherche Biomédicale, INSERM U955-E10 Créteil, France.
authors.forename: Ted Hung-Tse
authors.initials: TH
authors.lastname: Chang
authors.affiliation: Randall Division of Cell and Molecular Biophysics, King's College London London, UK.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Zammit
authors.affiliation: Institut Mondor de Recherche Biomédicale, INSERM U955-E10Créteil, France; Université Paris Est, Faculté de MedecineCréteil, France; Ecole Nationale Veterinaire d'AlfortMaison Alfort, France; Etablissement Français du SangCréteil, France; APHP, Hopitaux Universitaires Henri Mondor, DHU Pepsy and Centre de Référence des Maladies Neuromusculaires GNMHCréteil, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Relaix
keywords: ephrins; myogenesis; satellite cells; skeletal muscle; zinc fingers