title: Aryl hydrocarbon receptor-dependent enrichment of a megakaryocytic precursor with a high potential to produce proplatelets.
abstract: The mechanisms regulating megakaryopoiesis and platelet production (thrombopoiesis) are still incompletely understood. Identification of a progenitor with enhanced thrombopoietic capacity would be useful to decipher these mechanisms and to improve our capacity to produce platelets in vitro. Differentiation of peripheral blood CD34(+) cells in the presence of bone marrow-human mesenchymal stromal cells (MSCs) enhanced the production of proplatelet-bearing megakaryocytes (MKs) and platelet-like elements. This was accompanied by enrichment in a MK precursor population exhibiting an intermediate level of CD41 positivity while maintaining its expression of CD34. Following sorting and subculture with MSCs, this CD34(+)CD41(low) population was able to efficiently generate proplatelet-bearing MKs and platelet-like particles. Similarly, StemRegenin 1 (SR1), an antagonist of the aryl hydrocarbon receptor (AhR) transcription factor known to maintain CD34 expression of progenitor cells, led to an enriched CD34(+)CD41(low) fraction and to an increased capacity to generate proplatelet-producing MKs and platelet-like elements ultrastructurally and functionally similar to circulating platelets. The effect of MSCs, like that of SR1, appeared to be mediated by an AhR-dependent mechanism because both culture conditions resulted in repression of its downstream effector CYP1B1. This newly described isolation of a precursor exhibiting strong MK potential could be exploited to study normal and abnormal thrombopoiesis and for in vitro platelet production.
authors.affiliation: Unité Mixte de Recherche (UMR) S949 INSERM, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France; Université de Strasbourg, Strasbourg, France;
authors.forename: Catherine
authors.initials: C
authors.lastname: Strassel
authors.affiliation: Unité Mixte de Recherche (UMR) S949 INSERM, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France; Université de Strasbourg, Strasbourg, France;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Brouard
authors.affiliation: Unité Mixte de Recherche (UMR) S949 INSERM, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France; Université de Strasbourg, Strasbourg, France;
authors.forename: Lea
authors.initials: L
authors.lastname: Mallo
authors.affiliation: Unité Mixte de Recherche (UMR) S949 INSERM, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France; Université de Strasbourg, Strasbourg, France;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Receveur
authors.affiliation: Unité Mixte de Recherche (UMR) S949 INSERM, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France; Université de Strasbourg, Strasbourg, France;
authors.forename: Pierre
authors.initials: P
authors.lastname: Mangin
authors.affiliation: Unité Mixte de Recherche (UMR) S949 INSERM, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France; Université de Strasbourg, Strasbourg, France;
authors.forename: Anita
authors.initials: A
authors.lastname: Eckly
authors.affiliation: Unité de Pharmacogénomique, Service de Génétique, Institut Curie, Paris, France;
authors.forename: Ivan
authors.initials: I
authors.lastname: Bieche
authors.affiliation: UMR INSERM U917, Rennes, France; Université Rennes 1, Rennes, France; and Etablissement Français du Sang-Bretagne, Rennes, France.
authors.forename: Karin
authors.initials: K
authors.lastname: Tarte
authors.affiliation: Unité Mixte de Recherche (UMR) S949 INSERM, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France; Université de Strasbourg, Strasbourg, France;
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.affiliation: Unité Mixte de Recherche (UMR) S949 INSERM, Strasbourg, France; Etablissement Français du Sang-Alsace, Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France; Université de Strasbourg, Strasbourg, France;
authors.forename: François
authors.initials: F
authors.lastname: Lanza
mesh_terms: D018952:Antigens, CD34 / Q000032:analysis; D001792:Blood Platelets / Q000166:cytology; D002469:Cell Separation; D002478:Cells, Cultured; D018920:Coculture Techniques; D016895:Culture Media, Serum-Free; D065633:Cytochrome P-450 CYP1B1 / Q000502:physiology; D006801:Humans; D016130:Immunophenotyping; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology*; D010976:Platelet Count; D040201:Platelet Membrane Glycoprotein IIb / Q000032:analysis; D011687:Purines / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D015398:Signal Transduction; D034061:Thrombopoiesis / Q000502:physiology*
chemical_list: D018952:Antigens, CD34; D016895:Culture Media, Serum-Free; D040201:Platelet Membrane Glycoprotein IIb; D011687:Purines; D018336:Receptors, Aryl Hydrocarbon; C552240:StemRegenin 1; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1