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    Blood coagulation: Molecular switches guide blood forming cells

    06/15/2017

    Scientists from the University of Würzburg successfully elucidated new details about a circuit regulating platelet biogenesis. These important findings could contribute to a better understanding of the mechanism leading to bleeding disorders.

    Mikroskopaufnahme von intaktem Knochenmarkgewebe von Mäusen. Im normalen Zustand lagern sich die reifen Megakaryozyten (grün) im Knochenmark an die Gefäßwand (rot) an und geben ihre neuen Blutplättchen zielgerichtet in die Blutbahn ab. Zellkerne sind
    Confocal microscope image of intact murine bone marrow. Under normal conditions the mature megakaryocyte (green) attaches to the blood vessel (red) and releases new platelets into the blood stream. The cell nuclei are shown in blue. (Photo: AG Nieswandt) Confocal microscope image of murine bone marrow under defective conditions. The lack of the Rho-GTPase ´RhoA´ in megakaryocytes (green) disrupts important molecular switches leading to transmigration of an intact megakaryocyte in the blood vessel (red). This leads to a dramatic impairment of platelet biogenesis. The cell nuclei are shown in blue. (Photo: AG Nieswandt)

    Platelets play a crucial role in hemostasis. At sites of vascular damage they attach to the subendothelial matrix, form a plug that seals the wound and contribute to tissue repair. Due to their short lifespan, new platelets need to be constantly generated. To this end, giant precursor cells in the bone marrow, so-called megakaryocytes, undergo a complex maturation process and finally release platelets into the bloodstream.

    Defects in platelet biogenesis can result in dramatically decreased numbers or malfunctioning of circulating platelets, thus affecting hemostasis in patients. Unfortunately, the detailed mechanisms regulating megakaryocyte maturation and platelet biogenesis still remain elusive.

    Modifications cause drastic consequences

    Researchers from the Rudolf Virchow Centre for Experimental Biomedicine and the University Hospital Würzburg now succeeded in identifying a decisive regulatory circuit in platelet biogenesis. The group of Prof. Bernhard Nieswandt was able to decipher vital regulating factors in megakaryocytes.

    Small proteins, the Rho-GTPases, serve as molecular switches in the regulation of important cellular functions such as maturation, as well as orientation towards the blood vessels. Thus, the RHo-GTPases allow megakaryocytes to properly produce platelets.

    'We could show that the complete absence or even a defect of these switches disrupts the orientation of the megakaryocyte, which then transmigrate through the blood vessel.´ says Nieswandt, director of the study.

    Indeed, under these conditions normal platelet biogenesis is abolished, leading to a drastic decrease in platelet count and bleeding complications in mice. These astonishing findings built the basis for a new understanding of platelet generation in bone marrow and most likely also provide new insights into the development of other blood cells.

    Therapeutical approach in bleeding disorders

    The discovery of this Rho-GTPase-dependent regulatory circuit in platelet biogenesis encourages the scientists to gain new insights in bleeding disorders, such as the Bernard-Soulier Syndrome. Patients suffering from this disorder endure a severe reduction of the platelet count, which is accompanied by a life-long profound bleeding complication. ´Our results open the way for new therapeutic approaches to treat diseases which are connected to defective platelet biogenesis.´ hopes Nieswandt.

    The scientists recently published their new findings together with other international researchers in the journal Nature Communications.

    Dütting, S. et al. (2017). A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis. Nature Communications. 8, 15838 doi: 10.1038/ncomms15838

    Websites

    http://www.rudolf-virchow-zentrum.de/home.html

    http://www.virchow.uni-wuerzburg.de/lab_pages/nieswandt/

    Contact

    Prof. Dr. Bernhard Nieswandt (Chair Experimental Biomedicine – Vascular Medicine, Rudolf-Virchow-Center), T +49 (0)931/ 31-80405, bernhard.nieswandt@virchow.uni-wuerzburg.de

    Katja Aurbach (PhD student, Dept. Experimental Biomedicine - Vascular Medicine), T +49 (0)931/ 31-99813, aurbach_K1@ukw.de

    Dr. Frank Sommerlandt (Public Science Center, Rudolf-Virchow-Center), T +49 (0)931 31-88449, frank.sommerlandt@uni-wuerzburg.de

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