Murine platelet production is suppressed by S1P release in the hematopoietic niche, not facilitated by blood S1P sensing
| Autor: | Najet Debili, Benoit Decouture, Sylvain Provot, Mari Kono, Eric Camerer, Ludovic Couty, Richard L. Proia, Maria L. Allende, Boubacar Mariko, Erica De Candia, Sonia Poirault-Chassac, Hira Niazi, Pierre-Louis Tharaux, Pierre Hadrien Becker, Véronique Baudrie, Christilla Bachelot-Loza, Rameez Ishaq, Nesrine Zoghdani, Anja Nitzsche, Alexandre Leuci, Yetki Aslan, Salome L. Gazit, Jerold Chun, Ammar Benarab, Patrice Therond, Pascale Gaussem |
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| Přispěvatelé: | Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Innovations thérapeutiques en hémostase (IThEM - U1140), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda], University of Segou, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Saclay, Hôpital Lariboisière, Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Bicêtre, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Laboratoire d'Etudes des Techniques et Instruments d'Analyse Moleculaire (LETIAM), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11), Università cattolica del Sacro Cuore [Roma] (Unicatt), Sanford Burnham Prebys Medical Discovery Institute, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), The Leducq Foundation (SphingoNet) (R.L.P. and E.C.), Fondation de France (E.C.), Higher Education Commission, Pakistan (H.N. and R.I.), ANR-10-MIDI-0003,GROVI,La règlulation de l'intégrité vasculaire par les GPCRs(2010), Camerer, Eric, MECANISMES INTEGRES DE L'INFLAMMATION - La règlulation de l'intégrité vasculaire par les GPCRs - - GROVI2010 - ANR-10-MIDI-0003 - MI2 - VALID |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology
Blood Platelets 0301 basic medicine [SDV]Life Sciences [q-bio] Thrombopoiesis Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Sphingosine megakaryocytes Settore MED/04 - PATOLOGIA GENERALE Animals Platelet Stem Cell Niche Sphingosine-1-Phosphate Receptors S1PR1 S1PR2 Megakaryopoiesis Mice Knockout [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology sphingolipids Chemistry organic chemicals Sphingosine Kinase 2 [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology Hematology Platelets and Thrombopoiesis Platelet production Cell biology [SDV] Life Sciences [q-bio] SPHK2 030104 developmental biology S1P receptors lipids (amino acids peptides and proteins) Lysophospholipids 030217 neurology & neurosurgery [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology Signal Transduction |
| Zdroj: | Blood Advances Blood Advances, The American Society of Hematology, 2019, 3 (11), pp.1702-1713. ⟨10.1182/bloodadvances.2019031948⟩ Blood Advances, 2019, 3 (11), pp.1702-1713. ⟨10.1182/bloodadvances.2019031948⟩ |
| ISSN: | 2473-9529 2473-9537 |
| Popis: | International audience; Key points • The vascular S1Pgradient is dispensablefor platelet formationin mice• Instead, local S1P production restrains megakaryopoiesis via S1P 1 and can further suppress platelet production via S1P 2 when deregulated. AbstractThe bioactive lipid mediator sphingosine 1-phosphate (S1P) was recently assigned critical roles in platelet biology: whereas S1P 1 receptor-mediated S1P gradient sensing was reported to be essential for directing proplatelet extensions from megakaryocytes (MKs) toward bone marrow sinusoids, MK sphingosine kinase 2 (Sphk2)-derived S1P was reported to further promote platelet shedding through receptor-independent intracellular actions, and platelet aggregation through S1P 1. Yet clinical use of S1P pathway modulators including fingolimod has not been associated with risk of bleeding or thrombosis. We therefore revisited the role of S1P in platelet biology in mice. Surprisingly, no reduction in platelet counts was observed when the vascular S1P gradient was ablated by impairing S1P provision to plasma or S1P degradation in interstitial fluids, nor when gradient sensing was impaired by S1pr1 deletion selectively in MKs. Moreover, S1P 1 expression and signaling were both undetectable in mature MKs in situ, and MK S1pr1 deletion did not affect platelet aggregation or spreading. When S1pr1 deletion was induced in hematopoietic progenitor cells, platelet counts were instead significantly elevated. Isolated global Sphk2 deficiency was associated with thrombocytopenia, but this was not replicated by MK-restricted Sphk2 deletion and was reversed by compound deletion of either Sphk1 or S1pr2, suggesting that this phenotype arises from increased S1P export and S1P 2 activation secondary to redistribution of sphingosine to Sphk1. Consistent with clinical observations, we thus observe no essential role for S1P 1 in facilitating platelet production or activation. Instead, S1P restricts megakaryopoiesis through S1P 1 , and can further suppress thrombo-poiesis through S1P 2 when aberrantly secreted in the hematopoietic niche. |
| Databáze: | OpenAIRE |
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