title: Transfer of differentiation signal by membrane microvesicles harboring hedgehog morphogens.
abstract: Hedgehog (Hh) proteins are considered diffusible morphogens that can be membrane anchored, playing an essential role during development. Here we show that Hh morphogens are associated with microvesicles (MVs) shed from the plasma membrane of apoptotic/stimulated T cells. Hh+ MVs induced differentiation of human K562 pluripotent erythroleukemic cells toward megakaryocytic lineage, as testified to by the expression of alpha(IIb)beta3 integrin and CD42b and changes in the cell cycle. Blocking Hh pathway with either cyclopamine, neutralizing antibodies, or inhibitors of the protein kinase A pathway resulted in the inhibition of these effects. Activation of Hh signaling by SAG, a synthetic agonist, mimicked effects of Hh+ MVs on K562 cells. Human Hh+ MVs, circulating in vivo or derived from apoptotic/stimulated lymphocytes from healthy and diabetic individuals, elicited K562 cell differentiation, also inhibited by cyclopamine. In addition, Hh+ MV-treated primary human CD34+ cells presented an increase of CD41+ CD42- and CD41+ CD42+ megakaryocytic populations with an increase of corresponding polyploidy, both being reduced by blockers of the Hh pathway. Because virtually all cell types undergo plasma membrane remodeling when stimulated, derived MVs can therefore be considered true vectors in the transfer of morphogen-borne biologic information to remote responsive cells, and thereby contribute to the maintenance of homeostasis.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 770, Hôpital de Bicêtre, France.
authors.forename: María Carmen
authors.initials: MC
authors.lastname: Martínez
authors.forename: Fréderic
authors.initials: F
authors.lastname: Larbret
authors.forename: Fatiha
authors.initials: F
authors.lastname: Zobairi
authors.forename: Josée
authors.initials: J
authors.lastname: Coulombe
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Martial
authors.initials: M
authors.lastname: Ruat
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Freyssinet
mesh_terms: D018952:Antigens, CD34 / Q000276:immunology; D017209:Apoptosis; D002453:Cell Cycle / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D003920:Diabetes Mellitus / Q000276:immunology*; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D021962:Membrane Microdomains / Q000276:immunology*; D009024:Morphogenesis; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000502:physiology
chemical_list: D018952:Antigens, CD34; D053823:Hedgehog Proteins