title: SP/drug efflux functionality of hematopoietic progenitors is controlled by mesenchymal niche through VLA-4/CD44 axis.
abstract: Hematopoiesis is orchestrated by interactions between hematopoietic stem/progenitor cells (HSPCs) and stromal cells within bone marrow (BM) niches. Side population (SP) functionality is a major characteristic of HSPCs related to quiescence and resistance to drugs and environmental stresses. At steady state, SP cells are mainly present in the BM and are mostly absent from the circulation except in stress conditions, raising the hypothesis of the versatility of the SP functionality. However, the mechanism of SP phenotype regulation is unclear. Here we show for the first time that the SP functionality can be induced in lin(-) cells from unmobilized peripheral blood after nesting on mesenchymal stromal cells (MSCs). This MSC-induced SP fraction contains HSPCs as demonstrated by their (i) CD34(+) cell percentage, (ii) quiescent status, (iii) in vitro proliferative and clonogenic potential, (iv) engraftment in NSG (NOD SCID gamma chain) mice and (v) stemness gene expression profile. We demonstrate that SP phenotype acquisition/reactivation by circulating lin(-) cells is dependent on interactions with MSCs through VLA-4/α4β1-integrin and CD44. A similar integrin-dependent mechanism of SP phenotype acquisition in acute myeloid leukemia circulating blasts suggests an extrinsic regulation of ATP-binding cassette-transporter activity that could be of importance for a better understanding of adhesion-mediated chemoresistance mechanisms.
authors.affiliation: 1] Service d'hématologie, HIA Percy, Clamart, France [2] CTS des Armées, Clamart, France.
authors.forename: J-V
authors.initials: JV
authors.lastname: Malfuson
authors.affiliation: CTS des Armées, Clamart, France.
authors.forename: L
authors.initials: L
authors.lastname: Boutin
authors.affiliation: 1] Inserm U972, Villejuif, France [2] IFR89, Institut André Lwoff, Villejuif, France.
authors.forename: D
authors.initials: D
authors.lastname: Clay
authors.affiliation: CTS des Armées, Clamart, France.
authors.forename: C
authors.initials: C
authors.lastname: Thépenier
authors.affiliation: 1] Inserm U972, Villejuif, France [2] Univ Paris-Sud, Villejuif, France.
authors.forename: C
authors.initials: C
authors.lastname: Desterke
authors.affiliation: 1] Inserm U972, Villejuif, France [2] Univ Paris-Sud, Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: Torossian
authors.affiliation: 1] Inserm U972, Villejuif, France [2] Univ Paris-Sud, Villejuif, France.
authors.forename: B
authors.initials: B
authors.lastname: Guerton
authors.affiliation: 1] Inserm U972, Villejuif, France [2] Univ Paris-Sud, Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Anginot
authors.affiliation: 1] Service d'hématologie, HIA Percy, Clamart, France [2] Ecole du Val de Grâce, Paris, France.
authors.forename: T
authors.initials: T
authors.lastname: de Revel
authors.affiliation: 1] CTS des Armées, Clamart, France [2] Ecole du Val de Grâce, Paris, France.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Lataillade
authors.affiliation: 1] Inserm U972, Villejuif, France [2] IFR89, Institut André Lwoff, Villejuif, France [3] Univ Paris-Sud, Villejuif, France.
authors.forename: M-C
authors.initials: MC
authors.lastname: Le Bousse-Kerdilès
mesh_terms: D000818:Animals; D019008:Drug Resistance, Neoplasm; D019204:GTP-Binding Proteins / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D018960:Hyaluronan Receptors / Q000502:physiology*; D039041:Integrin alpha4beta1 / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction; D019061:src-Family Kinases / Q000502:physiology
chemical_list: C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D039041:Integrin alpha4beta1; D019061:src-Family Kinases; D019204:GTP-Binding Proteins