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Blood, 1 November 2006, Vol. 108, No. 9, pp. 3012-3020. Prepublished online as a Blood First Edition Paper on June 20, 2006; DOI 10.1182/blood-2006-04-019109.
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Transfer of differentiation signal by membrane microvesicles harboring hedgehog morphogensFrom the Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 770, Hôpital de Bicêtre, France; Université Louis Pasteur, Faculté de Médecine, Institut d'Hématologie et d'Immunologie, Strasbourg, France; INSERM, Unité 790, Institut Gustave Roussy, Villejuif, France; and Centre National de la Recherche Scientifique (CNRS) Unité Propre de Recherche (UPR) 9040, Institut Fédératif de Recherche (IFR) 2118, Laboratoire de Neurobiologie Cellulaire et Moléculaire, Gif-sur-Yvette, France.
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
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| Copyright © 2006 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
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3 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. 
