Research Focus & Cooperations of the WG Seifert
Here you find an overview of the current research projects and the respective cooperations.
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The focus of the research is to analyze the pathomechanisms of endothelial dysfunction and a modulation of endothelial cell properties by interaction with soluble mediators and other cell types (e.g., mesenchymal stromal cells). In disorders of endothelial function, the involvement of autoantibodies against endothelial cell antigens and of extracellular vesicles in blood plasma are investigated in particular.
Endothelial dysfunction in the pathogenesis of ME/CFS
Several studies have shown that endothelial dysfunction (ED) plays an important role in the disease pathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). ME/CFS is an autoimmune, multisystemic, chronic disease with an estimated prevalence of 0.3%. Patients suffer from severe fatigue, cognitive dysfunction, and chronic pain that drastically affects their quality of life. Despite significant progress in understanding ME/CFS disease in recent years, the pathomechanism is still poorly understood. However, there is evidence that immune and autonomic nervous system dysregulation, metabolic disorders, and ED are also involved. Impaired autonomic function has been associated with ED characterized by impaired vascular endothelial cell response, likely leading to impaired blood flow regulation and hypoxia during exercise.
We aim through our studies to understand the pathophysiology of ED in ME/CFS patients and to find reliable biomarkers that both facilitate diagnosis and lead to the identification of potential therapeutic molecules. To this end, we are investigating the effects of serum components on the functional and regenerative properties of endothelial cells in patients with ME/CFS after an infectious trigger. These factors include autoantibodies, various other serum proteins, but also extracellular vesicles. In a recent study with post-COVID-19 ME/CFS patients, we demonstrated that serum components contribute to dysregulated endothelial cell function in vitro (Flaskamp et al. 2022). In future studies, we aim to further investigate the mechanisms involved.
Our group closely collaborates with the team of Prof. Carmen Scheibenbogen (Institute of Medical Immunology, Immunodeficiency Outpatient Clinic) and Charité Fatique Centrum; (CFC)
Modulation of endothelial cell properties in therapies with stromal cells
Therapeutic approaches involving intramuscular and intravenous delivery of mesenchymal stromal cells require knowledge of the specific milieu into which the cells are injected. After injection, endothelial and immune cells are among the first cell types they encounter. It is likely that the microenvironment in diseased patients, activates and damages both cells present in the tissue and circulating cells, such as endothelial cells. Therefore, we analyze functional changes in endothelial progenitor cells from patients receiving stromal cell therapy after significant manifestation of atherosclerotic disease. In addition, we simulate in vitro the interaction of stromal cells with endothelial and immune cells under different experimental conditions to better understand the regenerative impact of stromal cell therapy on activated or damaged endothelial cells.
Extracellular vesicles: Potential modulators of endothelial cell function and diagnostic markers
In the last decade, extracellular vesicles (EV) have been identified as potent paracrine mediators that elicit beneficial effects regarding enhanced regeneration after their release by various regenerative cells, such as mesenchymal stromal cells. We investigated the characteristics and functional effects of EV from cardiac mesenchymal cells, in particular their pro-angiogenic, as well as immunomodulatory potential. Here, we analyzed the composition of EVs in terms of their protein and miRNA spectrum (Beez et al. 2019)
From serum of ME/CFS patients and healthy control subjects, we isolate extracellular vesicles with a diameter <130 nm by size exclusion chromatogaphy and analyze the phenotypic properties, miRNA expression profile and protein composition. Furthermore, functional effects of the vesicles on the secretion profiles of human endothelial cells (e.g. HUVEC), as well as their influence on nitric oxide production, vascular formation and wound healing in vitro are also investigated.
- Prof. Carmen Scheibenbogen (Charité Berlin, Institute of Medical Immunology)
- Prof. Wolfram Döhner (Charité Berlin, BCRT)
- Prof. Hans-Dieter Volk (Charité Berlin, Institute of Medical Immunology & BCRT)
- Prof. Katja Schenke-Layland (NMI, University Tübingen)
- Prof. Ulrich Stock (Brompton Hospital, London, UK)
- Prof. Dirk Strunk (Paracelsus Medizinische Privatuniversität Salzburg, A)
- Prof. Michael Sittinger, Dr. Marion Haag (Charité Berlin, BCRT)
- PD Dr. Sophie van Linthout (Charité Berlin, BCRT)
- Dr. Oliver Klein (Charité Berlin, BCRT)
- Dr. Timo Nazari-Shafti (Charité Berlin, DHZB & BCRT)
- Dr. Sven Geissler (Charité Berlin, Julius-Wolff-Institut & BCRT)
- Dr. Manfred Gossen (HZG, Teltow)