Thrombo-inflammatory diseases, such as ischemic stroke, are major causes of death and disability worldwide.
The distinct molecular mechanisms how platelets contribute to thrombo-inflammatory processes remain largely unknown. We could already demonstrate that platelet secretion is an important mediator of thrombo-inflammation in the ischemic brain. Moreover, targeting the early steps of platelet adherence to the vessel wall via glycoprotein (GP)Ib/von Willebrand factor (VWF) interactions not only reduced thrombus burden in the cerebral microvasculature, but also limited the local inflammatory response in the ischemic organ. Besides platelets, also endothelial cells (the major component of the blood brain barrier) and leukocytes, in particular T cells, play a central role in ischemia/reperfusion (I/R) injury. Accordingly, lack of T cells results in dramatically reduced infarct sizes.
To develop novel treatment strategies, it is necessary to understand the detrimental interplay between thrombotic and inflammatory circuits, which would only be possible if the cellular interactions can be visualized. In order to image thrombo-inflammation with different advanced imaging modalities, we collaborate intensively with the Bio-Imaging Center. Together, we have established optical clearing and labelling protocols for light-sheet-fluorescence microscopy (LSFM), which allows us to visualize the whole vascular tree and the localization of platelets and/or immune cells within the brain vasculature in a whole organ setting. In addition, we benefit from confocal and two-photon intravital microscopy to image dynamic interactions within the ischemic organ with a high temporal and spatial resolution. Our complementary approaches will provide a better understanding of the pathomechanisms, taking place in the vascular compartment, which lead to organ damage following I/R injury.
The established imaging techniques are not only used to study thrombo-inflammation in the brain vasculature, but are also utilized to study other dynamic processes like for example the production of platelet in the bone marrow (thrombopoiesis).
Brown HC, Beck S, Navarro S, Di Y, Soriano Jerez EM, Kaczmarzyk J, Thomas SG, Mirakaj V, Watson SP, Nieswandt B, Stegner D. Antibody-mediated depletion of human CLEC-2 in a novel humanised mouse model. Blood Adv. 2022. DOI: 10.1182/bloodadvances.2021006463
Stegner D, Göb V, Krenzlin V, Beck S, Hemmen K, Schuhmann MK, Schörg BF, Hackenbroch C, May F, Burkard P, Pinnecker J, Zernecke A, Rosenberger P, Greinacher A, Pichler BJ, Heinze KG, Stoll G, Nieswandt B. Foudroyant cerebral venous (sinus) thrombosis triggered through CLEC-2 and GPIIb/IIIa dependent platelet activation. Nat Cardiovasc Res. 2022; 1:132-141. DOI: 10.1038/s44161-021-00017-1
Heil HS, Aigner M, Maier S, Gupta P, Evers LMC, Göb V, Kusch C, Meub M, Nieswandt B, Stegner D*, Heinze KG*. Mapping densely packed αIIbβ3 receptors in murine blood platelets with expansion microscopy. Platelets. 2022; 2:1-10. DOI: 10.1080/09537104.2021.2023735
Göb V, Voll MG, Zimmermann L, Hemmen K, Stoll G, Nieswandt B, Schuhmann MK, Heinze KG, Stegner D. Infarct growth precedes cerebral thrombosis following experimental stroke in mice. Sci Rep. 2021; 11:22887. DOI: 10.1038/s41598-021-02360-
Schuhmann MK, Stoll G, Bieber M, Vögtle T, Hofmann S, Klaus V, Kraft P, Seyhan M, Kollikowski AM, Papp L, Heuschmann PU, Pham M, Nieswandt B, Stegner D. CD84 Links T Cell and Platelet Activity in Cerebral Thrombo-Inflammation in Acute Stroke. Circ Res. 2020;127:1023-35. DOI: 10.1161/CIRCRESAHA.120.316655
Heib T, Gross C, Müller ML, Stegner D*, Pleines I*. Isolation of murine bone marrow by centrifugation or flushing for the analysis of hematopoietic cells - a comparative study. Platelets. 2020; 32:601-607. DOI: 10.1080/09537104.2020.1797323
Stegner D, Hofmann S, Schuhmann MK, Kraft P, Herrmann AM, Popp S, Höhn M, Popp M, Klaus V, Post A, Kleinschnitz C, Braun A, Meuth SG, Lesch KP, Stoll G, Kraft R, Nieswandt B. Loss of Orai2-Mediated Capacitative Ca(2+) Entry Is Neuroprotective in Acute Ischemic Stroke. Stroke. 2019;50:3238-45. DOI: 10.1161/STROKEAHA.119.025357
Gorelashvili MG, Angay O, Hemmen K, Klaus V, Stegner D*, Heinze KG*. Megakaryocyte volume modulates bone marrow niche properties and cell migration dynamics. Haematologica. 2019; 105:895-904. DOI: 10.3324/haematol.2018.202010
Stegner D, van Eeuwijk JMM, Angay O, Gorelashvili MG, Semeniak D, Pinnecker J, Schmithausen P, Meyer I, Friedrich M, Dütting S, Brede C, Beilhack A, Schulze H, Nieswandt B, Heinze KG. Thrombopoiesis is spatially regulated by the bone marrow vasculature. Nat Commun. 2017; 8:127. DOI: 10.1038/s41467-017-00201-7
Beck S, Leitges M, Stegner D. Protein kinase Cι/λ is dispensable for platelet function in thrombosis and hemostasis in mice. Cell Signal. 2017, 38:223-9. DOI: 10.1016/j.cellsig.2017.07.015
W2 Professor of Vascular Imaging
|since 2021||W2 Professor of Vascular Imaging at the Rudolf Virchow Center|
|since 2018||Scientific secretary of the collaborative research center SFB/TR 240 and and project leader in the SFB/TR 240 (TP B06 and B08)|
|2016 – 2021||Junior Group Leader Vascular Imaging at the Institute for Experimental Biomedicine of the University Hospital Würzburg|
|2016 – 2017||Scientific secretary of the collaborative research center SFB 688|
|2014 – 2016||Postdoctoral Fellow at the Rudolf Virchow Center of the University of Würzburg with Prof. B. Nieswandt|
|2014 – 2017||Project leader within the collaborative research center 688 (SFB 688 – TP B07)|
|2012 – 2013||Postdoctoral Fellow at the Department of Neurology of the University Hospital Würzburg with Prof. G. Stoll|
|2011 – 2012||Postdoctoral Fellow at the Department of Experimental Biomedicine at the University Hospital Würzburg with Prof. B. Nieswandt|
|2011||PhD (Dr. rer. nat.) in Experimental Biomedicine, University of Würzburg|
|2006||Diploma in biochemistry at the University of Bayreuth|
Awards and scholarships
|2015, 2014, 2013||Young Investigator Award of the International Society of Thrombosis and Haemostasis (ISTH)|
|2007 - 2011|| |
Doctoral Fellowship of the Graduate School of Life Sciences, University of Würzburg