Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-17079 Wissenschaftlicher Artikel Dütting, Sebastian; Gaits-Iacovoni, Frederique; Stegner, David; Popp, Michael; Antkowiak, Adrien; van Eeuwijk, Judith M.M.; Nurden, Paquita; Stritt, Simon; Heib, Tobias; Aurbach, Katja; Angay, Oguzhan; Cherpokova, Deya; Heinz, Niels; Baig, Ayesha A.; Gorelashvili, Maximilian G.; Gerner, Frank; Heinze, Katrin G.; Ware, Jerry; Krohne, Georg; Ruggeri, Zaverio M.; Nurden, Alan T.; Schulze, Harald; Modlich, Ute; Pleines, Irina; Brakebusch, Cord; Nieswandt, Bernhard A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis Blood platelets are produced by large bone marrow (BM) precursor cells, megakaryocytes (MKs), which extend cytoplasmic protrusions (proplatelets) into BM sinusoids. The molecular cues that control MK polarization towards sinusoids and limit transendothelial crossing to proplatelets remain unknown. Here, we show that the small GTPases Cdc42 and RhoA act as a regulatory circuit downstream of the MK-specific mechanoreceptor GPIb to coordinate polarized transendothelial platelet biogenesis. Functional deficiency of either GPIb or Cdc42 impairs transendothelial proplatelet formation. In the absence of RhoA, increased Cdc42 activity and MK hyperpolarization triggers GPIb-dependent transmigration of entire MKs into BM sinusoids. These findings position Cdc42 (go-signal) and RhoA (stop-signal) at the centre of a molecular checkpoint downstream of GPIb that controls transendothelial platelet biogenesis. Our results may open new avenues for the treatment of platelet production disorders and help to explain the thrombocytopenia in patients with Bernard-Soulier syndrome, a bleeding disorder caused by defects in GPIb-IX-V. 2017 Nature Communications 8 15838 urn:nbn:de:bvb:20-opus-170797 10.1038/ncomms15838 Theodor-Boveri-Institut für Biowissenschaften OPUS4-17059 Wissenschaftlicher Artikel Stegner, David; van Eeuwijk, Judith M.M.; Angay, Oğuzhan; Gorelashvili, Maximilian G.; Semeniak, Daniela; Pinnecker, Jürgen; Schmithausen, Patrick; Meyer, Imke; Friedrich, Mike; Dütting, Sebastian; Brede, Christian; Beilhack, Andreas; Schulze, Harald; Nieswandt, Bernhard; Heinze, Katrin G. Thrombopoiesis is spatially regulated by the bone marrow vasculature In mammals, megakaryocytes (MKs) in the bone marrow (BM) produce blood platelets, required for hemostasis and thrombosis. MKs originate from hematopoietic stem cells and are thought to migrate from an endosteal niche towards the vascular sinusoids during their maturation. Through imaging of MKs in the intact BM, here we show that MKs can be found within the entire BM, without a bias towards bone-distant regions. By combining in vivo two-photon microscopy and in situ light-sheet fluorescence microscopy with computational simulations, we reveal surprisingly slow MK migration, limited intervascular space, and a vessel-biased MK pool. These data challenge the current thrombopoiesis model of MK migration and support a modified model, where MKs at sinusoids are replenished by sinusoidal precursors rather than cells from a distant periostic niche. As MKs do not need to migrate to reach the vessel, therapies to increase MK numbers might be sufficient to raise platelet counts. 2017 Nature Communications 8 127 urn:nbn:de:bvb:20-opus-170591 10.1038/s41467-017-00201-7 Medizinische Klinik und Poliklinik II