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Ptk7-Deficient Mice Have Decreased Hematopoietic Stem Cell Pools As a Result of Deregulated Proliferation and Migration

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Ptk7-Deficient Mice Have Decreased Hematopoietic Stem Cell Pools As a Result of Deregulated Proliferation and Migration Ptk7-Deficient Mice Have Decreased Hematopoietic Stem Cell Pools as a Result of Deregulated Proliferation and Migration This information is current as Anne-Catherine Lhoumeau, Marie-Laure Arcangeli, Maria of September 24, 2021. De Grandis, Marilyn Giordano, Jean-Christophe Orsoni, Frédérique Lembo, Florence Bardin, Sylvie Marchetto, Michel Aurrand-Lions and Jean-Paul Borg J Immunol 2016; 196:4367-4377; Prepublished online 18 April 2016; Downloaded from doi: 10.4049/jimmunol.1500680 http://www.jimmunol.org/content/196/10/4367 Supplementary http://www.jimmunol.org/content/suppl/2016/04/16/jimmunol.150068 http://www.jimmunol.org/ Material 0.DCSupplemental References This article cites 55 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/196/10/4367.full#ref-list-1 Why The JI? Submit online. by guest on September 24, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Ptk7-Deficient Mice Have Decreased Hematopoietic Stem Cell Pools as a Result of Deregulated Proliferation and Migration Anne-Catherine Lhoumeau,*,†,‡,x Marie-Laure Arcangeli,†,‡,x,{,1 Maria De Grandis,†,‡,x,{ Marilyn Giordano,*,†,‡,x Jean-Christophe Orsoni,*,†,‡,x Fre´de´rique Lembo,*,†,‡,x Florence Bardin,†,‡,x,{ Sylvie Marchetto,*,†,‡,x Michel Aurrand-Lions,†,‡,x,{ and Jean-Paul Borg*,†,‡,x Hematopoietic stem cells (HSCs) located in adult bone marrow or fetal liver in mammals produce all cells from the blood system. At the top of the hierarchy are long-term HSCs endowed with lifelong self-renewal and differentiation properties. These features are controlled through key microenvironmental cues and regulatory pathways, such as Wnt signaling. We showed previously that PTK7, a tyrosine kinase receptor involved in planar cell polarity, plays a role in epithelial Wnt signaling; however, its function in hema- Downloaded from topoiesis has remained unexplored. In this article, we show that PTK7 is expressed by hematopoietic stem and progenitor cells, with the highest level of protein expression found on HSCs. Taking advantage of a Ptk7-deficient mouse strain, we demonstrate that loss of Ptk7 leads to a diminished pool of HSCs but does not affect in vitro or in vivo hematopoietic cell differentiation. This is correlated with increased quiescence and reduced homing abilities of Ptk7-deficient hematopoietic stem and progenitor cells, unraveling novel and unexpected functions for planar cell polarity pathways in HSC fate. The Journal of Immunology, 2016, 196: 4367–4377. http://www.jimmunol.org/ ematopoiesis is a biological process consisting of the particularly in the liver, during its earliest phases. Long-term production of all blood cell types from hematopoietic HSCs are characterized by their capacity to provide lifelong H stem cells (HSCs) located in the bone marrow (BM) of reconstitution of all blood cell lineages after transplantation into adult mammals. Fetal hematopoiesis occurs in different sites, lethally irradiated recipients, whereas short-term HSCs do so for only 8–10 wk. In the mouse, long-term HSCs belong to the LSK cell com- *Centre de Recherche en Cance´rologie de Marseille, Polarite´ Cellulaire, Signalisa- 2/low + + tion Cellulaire et Cancer “Equipe labellise´e Ligue Contre le Cancer,” INSERM, partment, as defined by the Lin Sca-1 c-Kit phenotype, U1068, Marseille F-13009, France; †Institut Paoli-Calmettes, Marseille F-13009, irrespective of their fetal liver (FL) or adult BM origin. Additional ‡ x France; CNRS, UMR7258, Marseille F-13009, France; Universite´ d’Aix- by guest on September 24, 2021 { markers, known as signaling lymphocytic activation molecules Marseille, Marseille F-13284, France; and Centre de Recherche en Cance´rologie de Marseille, Mole´cules d’Adhe´rence Jonctionnelles dans Host/Tumeur Interactions, (SLAMs), can be used to subdivide this compartment (1, 2). In- INSERM, U1068, Marseille F-13009, France deed, CD150+CD482 LSK cells contain ∼40% of HSCs with 1Current address: INSERM U967, Institut de recherche en radiobiologie cellulaire et long-term reconstitution potential in BM, as well as in FL (3). mole´culaire – Commissariat a` l’e´nergie atomique, Fontenay-aux-Roses F-92265, France. Hematopoiesis is a highly controlled multi-step process that relies on complex interaction networks involving cell surface re- ORCIDs: 0000-0001-6465-8723 (M.D.G.); 0000-0002-8361-3034 (M.A.-L.); 0000- 0001-8418-3382 (J.-P.B.). ceptors, growth factors, and adhesion molecules expressed by Received for publication March 23, 2015. Accepted for publication March 11, 2016. HSCs and their environment (4–8). Because HSCs generate mature This work was supported by Institut National du Cancer (INCa) (Projet Libre INCa hematopoietic cells, including immune cells, their replacement 2012-108), the Site de Recherche Inte´gre´e en Cance´rologie program (INCa- must be adjusted to homeostatic or stress conditions, such as in- Direction ge´ne´rale de l’offre de soins-INSERM 6038), and Canceropole Provence- fections, inflammation, or blood loss, and their expansion must be Alpes-Coˆte d’Azur (all to M.A.-L. and J.-P.B.). A.-C.L. and M.-L.A. were supported by la Fondation pour la Recherche Me´dicale. M.D.G. was supported by la Fondation controlled to avoid exhaustion. This control is made possible by de France. J.-P.B.’s laboratory is supported by INSERM, Institut Paoli-Calmettes, the coordinated regulation of quiescence, self-renewal, and dif- and La Ligue Nationale Contre le Cancer (“Equipe labellise´e”). J.-P.B. is a scholar at ferentiation through appropriate signals delivered by functional the Institut Universitaire de France. BM niches (9). HSCs are retained in these BM niches by cell A.-C.L. designed experiments, generated deficient mice, performed all experiments, and wrote the manuscript. M.D.G., M.G., F.L., F.B., and S.M. helped to perform surface molecules endowed with adhesive and/or signaling experiments. J.-C.O. generated deficient mice. M.-L.A., M.A.-L., and J.-P.B. de- functions expressed by HSCs. These receptors belong to different signed experiments and wrote the manuscript. protein families, including integrins (VLA-4) (10), Ig superfam- Address correspondence and reprint requests to Dr. Jean-Paul Borg, Centre de Re- ily adhesion molecules (6, 11), G protein–coupled receptors cherche en Cance´rologie de Marseille, Inserm, CNRS, Aix-Marseille Universite´, Institut Paoli-Calmettes, 27 bd Leı¨ Roure, BP 30059, 13273 Marseille cedex 09, (CXCR4) (12), and tyrosine kinase receptors (TIE2, c-Kit) (13– France. E-mail address: [email protected] 15), which interact with ligands present within the BM microen- The online version of this article contains supplemental material. vironment (16). The discovery of novel molecules implicated in Abbreviations used in this article: BM, bone marrow; CLP, common lymphoid pro- this multi-step program is of particular importance to grasping its genitor; DN, double negative; DP, double positive; E, embryonic day; EPO, erytho- complexity, to developing new strategies aimed at the regeneration poietin; ES, embryonic stem; FL, fetal liver; HSC, hematopoietic stem cell; HSPC, hematopoietic stem and progenitor cell; MPP, multipotent progenitor; MPP1, MPP of damaged hematopoietic tissues, and to understanding hemato- type 1; MPP2, MPP type 2; MPP3, MPP type 3; MPP4, MPP type 4; PCP, planar cell poietic diseases. polarity; RFI, ratio fluorescence intensity; SDF-1a, stromal-derived factor-1a; PTK7 is a planar cell polarity (PCP) receptor belonging to the Ig shRNA, short hairpin RNA; SLAM, signaling lymphocytic activation molecule. superfamily, and it plays important roles during development (17, Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 18). PCP is controlled by a noncanonical Wnt pathway, organizes www.jimmunol.org/cgi/doi/10.4049/jimmunol.1500680 4368 ROLE OF THE POLARITY PROTEIN PTK7 IN MURINE HEMATOPOIESIS polarization of many epithelial tissues and organs within the filtered using a 70-mm cell strainer (BD Falcon), and lysis of RBCs was plane, and drives cell migration and cell intercalation of non- done using ACK lysis buffer (0.15 M NH4Cl, 10 mM KHCO3, 0.1 mM epithelial cells, such as mesenchymal cells (19, 20). Ptk7-deficient Na2EDTA; Life Technologies) for 2 min at room temperature. Cells were spun and resuspended in PBS–2% FCS, with or without 0.125 mM EDTA mouse embryos show all signs of typical PCP defects, such as for staining. For blood samples, RBC lysis was done after staining using severe neural tube and abdomen closure defects with secondary BD FACS Lysing buffer solution (BD Biosciences), following the manu- development abnormalities (21). PTK7 is a type I protein com- facturer’s instructions. posed of seven Ig loops in its extracellular region, a transmem- For flow cytometry analysis and cell sorting, cells were stained with mAbs purchased from eBioscience or BioLegend against the following brane domain, and an intracellular region with a tyrosine kinase molecules: B220 (clone 6B2), CD3 (145-2C11), CD4 (RM4-5), CD8 (53-6.7), domain (17, 18, 22, 23). Although PTK7 is catalytically inactive, CD11b/Mac-1 (M1/70), CD11c (N418), CD16/32 (93), CD19 (6D5), CD24 the cytoplasmic domain containing the tyrosine kinase domain is (M1/69), CD34 (RAM34), CD45 (30F11), CD45.1/Ly5.1 (A20), CD45.2/ mandatory for receptor function in vitro and in vivo (24–27).
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