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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 research group focuses on the investigation of the interaction of human immune cells with different mesenchymal cell types and their released extracellular vesicles, as well as with complex tissue matrices. Furthermore, the experimental work focuses on the understanding and modulation of the immune response against endothelial cells and the development of endothelial dysfunction in chronic diseases.

Regenerative therapies and their mechanisms

Regenerative cell types: Cardiac, Placenta and Umbilical Cord-derived cells and tenocytes

Expression of Ki67 (purple) and Vimentin (yellow) on human atrial appendage-derived cells. Nuclei were stained with 4‘-6-Diamidino-2-phenylindol (DAPI; blue).

Currently, almost all medical specialties are in need of innovative therapy strategies for diseases, for example insufficient wound healing, impaired organ function or vascular damage. Over the last decade cell-based therapies have gained increasing interest in this context as tools to induce regenerative processes in situ or to enable the ex vivo generation of functional tissues. Our lab is particularly interested in stromal cells derived from tissues such as placenta, umbilical cord, tendon and cardiac tissue. These cell types are interesting candidates to promote healing not only by inducing self-renewing processes, but also by modulating the immune system towards an anti-inflammatory and regenerative state. Nowadays, non-autologous (allogeneic) application of cryopreserved cells and tissues as an off-the-shelf product is highly preferred, since it enables immediate availability and the treatment of a substantial number of patients. In order to provide these products, it is crucial to have a deep understanding of the underlying mechanism of action of stromal cells to ensure a fast and safe translation of this knowledge for the benefit of patients. However, application of foreign cell- and tissue-products poses the risk of rejection by the host’s immune system and the induction of unwanted immune reactions. For the safety of the patient, these issues must be solved before clinical translation. Therefore, it is our goal to assess the immunogenicity as well as immunomodulatory potential of promising mesenchymal cell types by using suitable in vitro and in vivo test systems.

Stromal-Endothelial Cell Interaction

ECFC and MSC driven vasculogenesis in Matrigel after subcutaneous implantation in a mouse model. Human CD31+ endothelial structures (green) are surrounded by α-SMA+ cells (red). Nuclei were stained with 4‘-6-Diamidino-2-phenylindol (DAPI; blue).Scale bar = 500 µm

Endothelial cell-based therapies support the regeneration of tissues damaged by ischemia and promote vascularization of tissue-engineered constructs. The availability of autologous endothelial progenitor cells in peripheral blood is often restricted in diseased patients. Furthermore, the specific endothelial progenitor cell fraction, the so-called Endothelial Colony Forming Cells (ECFC), may be functionally compromised. Therapeutically relevant numbers of endothelial progenitor cells can be isolated from a single umbilical cord. For the majority of patients, cells isolated from the umbilical cord would represent an allogeneic tissue source. We already showed that allogeneic ECFC from umbilical cord are indeed immunogenic and would, similarly to Human Umbilical Vein Cells (HUVEC), induce allogeneic immune responses after transplantation.

To cope with this we are investigating a novel cell therapeutic approach to modulate the immunity of ECFC by co-applying immunosuppressive Mesenchymal Stromal Cells (MSC). Notably, the combination of both cell types is reported to induce synergistic vasculogenic effects leading to an improved architecture of de novo induced vascular networks. In our lab, we address the question, how a combined allogeneic cell product of both cell types, is interacting with immune cells and impacts important immune mechanisms. A proper understanding would enable for the better assessment of the rejection potential of such ECFC/MSC constructs.

Extracellular Vesicles - a cell free therapeutic approach

Transmission microscopy image of extracellular vesicles isolated from cardiac mesenchymal stromal-like cells by sequential ultracentrifugation showing the typical morphology and the varying size of vesicles. Scale bar = 100 nm.

The beneficial interplay of regenerative and/or immune cells with each other is enabled by their capability to communicate. Those mechanisms might include either direct connections, such as tight junctions, or indirectly through the release of cytokines, chemokines, hormones or extracellular vesicles. In the last decade, extracellular vesicles (EVs) have been identified as potent paracrine mediators to initiate beneficial effects if released by regenerative cells. According to their size and differential biogenesis EVs are subdivided into apoptotic bodies (> 1 µm), microvesicles (0,1-1 µm) and the smallest subtype, exosomes (<0,1µm).

In our group, we are interested in evaluating the characteristics and the functional effects of EVs from cardiac derived mesenchymal-like cells, in particular their pro-angiogenic and immune modulatory potential. We analyse in detail the composition of the EV regarding their proteome miRNA pattern. In another project we focus on a deeper understanding of the EV´s role in regeneration processes and within the interplay of mesenchymal cells and immune cells in tendon tissue

Immunological screening of biomaterials for cardiovascular application - biological & synthetic scaffolds

Human macrophages cultured for 2 days on ice free cryopreserved aortic tissue (left) and on ECM protein coated electrospun matrix (right). Scale bars = 20 µm.

Biological and synthetic biomaterials are generated for the replacement of damaged and non-functional tissue in cardiovascular diseases, like heart valves and vascular grafts. The extensive evaluation of induced immune responses is an important issue and involves the first line innate mechanism (complement activation, granulocytes, monocytes/macrophages) and the adaptive responses by T cells.

Our lab is investigating biological scaffolds, such as vascular tissue cryopreserved by different methods (conventional and ice-free method). Additionally, different types of electrospun materials (synthetic grafts) generated by our collaboration partner (Lab of Prof. Katja Schenke-Layland; NMI, University Tübingen) are investigated as well as the impact of matrix functionalization by extracellular matrix proteins on their immunological compatibility. We have developed a set of different in vitro screening systems for all types of immune responses, including the activation, differentiation and polarization of granulocytes, monocytes and macrophages and dendritic cells, the proliferation and activation of T cells and endothelial cell activation

Endothelial cells in health and disease

Effects of stromal cell therapies on endothelial cells

Therapeutic approaches using intramuscular and intravenous delivery of stromal cells requires knowledge of the specific milieu the cells are injected in to. One of the first cell types these cell products encounter are endothelial and immune cells. The microenvironment in diseased patients is expected to activate and damage resident/circulating cells, like endothelial cells. Therefore, we analyse functional changes in endothelial progenitor cells from patients showing significant manifestation of arteriosclerotic disease receiving a stromal cell therapy. Additionally, we simulate in vitro the interaction of stromal cells with endothelial and immune cells in different experimental conditions to better understand the regenerative impact of stromal cell therapy on activated or damaged endothelial cells.

Endothelial dysfunction in pathogenesis of chronic fatigue syndrome (CFS)

Recently, it was found that peripheral endothelial dysfunction (ED) is highly likely to represent a central position in the disease pathogenesis of Chronic Fatigue Syndrome (CFS). CFS is an autoimmune, multisystem, chronic disease with an estimated prevalence of 0.2–0.3% and unknown etiology. Patients suffer from severe fatigue, cognitive dysfunction, chronic pain as well as flu-like symptoms which all drastically impair their life quality. The pathomechanism of CFS is not completely understood, but there is evidence that dysregulation of the immune and autonomic nervous system, metabolic disturbances and ED are involved. ED is characterized by alterations of endothelial cells resulting in reduced vasodilative response. It is a risk factor for cardiovascular diseases and patients with CFS have an increased cardiovascular morbidity and mortality.

In collaboration with the group of Prof. Carmen Scheibenbogen (Institute of Medical Immunology, Immune defect ambulance and Charité Fatigue Center) we aim to understand the pathophysiology of ED in CFS patients and to find reliable biomarkers facilitating diagnosis and discovery of potential therapeutic targets.

Collaborations

Our partners

  • Prof. Hans-Dieter Volk (Charité Berlin, Institute of Medical Immunology & BCRT)
  • Prof. Carmen Scheibenbogen (Charité Berlin, Institute of Medical Immunology)
  • Prof. Wolfram Döhner (Charité Berlin, BCRT)
  • Prof. Britt Wildemann (Experimental Trauma Surgery, University Hospital Jena)
  • Prof. Katja Schenke-Layland (NMI, University Tübingen)
  • Prof. Ulrich Stock (Brompton Hospital, London, UK)
  • Prof. Dirk Strunk (Paracelsus Medizinische Privatuniversität Salzburg, A)
  • PD Katharina Schallmoser (University Salzburg, A)
  • Prof. Michael Sittinger, Dr. Marion Haag (Charité Berlin, BCRT)
  • PD Dr. Sophie van Linthout/Dr. Kathleen Pappritz (Charité Berlin, BCRT)
  • Prof. Carsten Tschöpe (Charité Berlin, BCRT)
  • Dr. Franka Klatte-Schulz (Charité Berlin, Julius-Wolff-Institut)
  • Dr. Oliver Klein (Charité Berlin, BCRT)
  • Prof. Christof Stamm/ Dr. Timo Nazari-Shafti (Charité Berlin, DHZB & BCRT)
  • Dr. Andreas Kurtz (Charité Berlin, BCRT)
  • Dr. Sven Geissler (Charité Berlin, Julius-Wolff-Institut & BCRT)
  • Dr. Manfred Gossen (HZG, Teltow)

Contact details

Prof. Martina Seifert

t: +49 30 450 539 435
f: +49 30 450 539 933