TY  - JOUR
A1  - Dütting, Sebastian
A1  - Gaits-Iacovoni, Frederique
A1  - Stegner, David
A1  - Popp, Michael
A1  - Antkowiak, Adrien
A1  - van Eeuwijk, Judith M.M.
A1  - Nurden, Paquita
A1  - Stritt, Simon
A1  - Heib, Tobias
A1  - Aurbach, Katja
A1  - Angay, Oguzhan
A1  - Cherpokova, Deya
A1  - Heinz, Niels
A1  - Baig, Ayesha A.
A1  - Gorelashvili, Maximilian G.
A1  - Gerner, Frank
A1  - Heinze, Katrin G.
A1  - Ware, Jerry
A1  - Krohne, Georg
A1  - Ruggeri, Zaverio M.
A1  - Nurden, Alan T.
A1  - Schulze, Harald
A1  - Modlich, Ute
A1  - Pleines, Irina
A1  - Brakebusch, Cord
A1  - Nieswandt, Bernhard
T1  - A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis
JF  - Nature Communications
N2  - 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.
KW  - megakaryocytes
KW  - blood platelets
KW  - regulatory circuit downstream
KW  - glycoprotein Ib
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170797
VL  - 8
IS  - 15838
ER  - 
TY  - JOUR
A1  - Stegner, David
A1  - van Eeuwijk, Judith M.M.
A1  - Angay, Oğuzhan
A1  - Gorelashvili, Maximilian G.
A1  - Semeniak, Daniela
A1  - Pinnecker, Jürgen
A1  - Schmithausen, Patrick
A1  - Meyer, Imke
A1  - Friedrich, Mike
A1  - Dütting, Sebastian
A1  - Brede, Christian
A1  - Beilhack, Andreas
A1  - Schulze, Harald
A1  - Nieswandt, Bernhard
A1  - Heinze, Katrin G.
T1  - Thrombopoiesis is spatially regulated by the bone marrow vasculature
JF  - Nature Communications
N2  - 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.
KW  - bone marrow
KW  - megakaryocytes
KW  - thrombopoiesis
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170591
VL  - 8
IS  - 127
ER  -