Our research is focused on the cell biology of mesenchymal stromal cells (MSC) of different tissue origins. MSC populations have been described in various tissues. Based on their ability to give rise to different cell types (e.g. adipocytes, chondrocytes and osteoblasts) and their secretory potential they are of great interest in Regenerative Medicine. Our projects aim to decipher interactions of MSC with their environment, both in physiology and pathophysiology. Increasing the knowledge on such interactions as well as mechanisms of adaptation in course of degenerative diseases, will facilitate the development of new therapeutic approaches.
Currently, we are working on following topics:
Regulation of bone marrow stromal cells (BMSC) and regenerative processes by inflammatory factors
Inflammation is related to many skeletal disorders including osteoarthritis, osteoporosis, fractures, and general bone loss. However, our understanding of the behavior of the rare population of bone marrow stem and progenitor cells (BMSC) is limited. This project synthesizes concepts from stem cell biology, physiology, and bioengineering to study the relationships between MSC and their inflammatory (micro)environment e.g. in the bone fracture hematoma.
We are focused on three areas in skeletal stem cell physiology: 1) identification of BMSC properties in regeneration of bone and cartilage tissue, supporting marrow hematopoiesis and adipose tissue persistence; 2) evaluation of immune-modulatory features of BMSCs; 3) significance of hematoma factors in regulation of BMSCs stemness and interactions with immune cells. In addition, we also explore the BMSC production of extracellular vesicles and their regulatory potential (see below).
We have a particular interest in understanding how hematoma signals contribute to skeletal repair, and how perturbations of immune and hematopoietic systems influence bone healing. Our mouse bone defect model allows us to study the cellular milieu and interactions at the early stage of hematoma formation.
Immunomodulatory properties of mesenchymal stromal cell-derived extracellular vesicles
Noah Volkmann, Drenka Trivanovic, Andrea Knorz, Marietta Herrmann
Extracellular vesicles (EVs) are small lipid bilayer encoated vesicles that have gained more and more interest as diagnostical or therapeutic tools lately, specifically because of their role in intercellular communication. In this project, we analyze the role of mesenchymal stromal cell (MSC) derived EVs in MSC mediated immunomodulation. In addition, the characterization of MSC-derived EVs and the analysis of mechanisms of interaction with target-cells are main foci of this area of research.
The extracellular matrix environment of bone marrow stromal cells
The extracellular matrix (ECM) microenvironment, namely its chemical composition and mechanical characteristics, is proven to distinctively modulate cell behavior and subsequently the full tissue dynamics. Despite of decades of MSC research, little is known about these complex cell-matrix interactions, mainly due to the lack of meaningful in vitro models that mimic the structure and composition of native tissue.
In the group, we develop decellularized human bone derived constructs in order to study those interactions in different degrees of complexity (e.g. 2D coatings, 3D hydrogels and scaffolds). While using decellularized 2D-matrices we can achieve a simple and easily accessible system where MSC interactions with the native matrix can be studied; using 3D models, such as hydrogels or scaffolds obtained from decellularization of human bone, we are able to study patterns of MSC migration and 3D interactions with the material.
Additionally, there is a strong interest in the group to study further the influence of external forces, such as sheer stress and compression loading. In collaboration with the Tissue Engineering and Regenerative Medicine (TERM) department, we apply a bioreactor system to specifically study the influence of dynamic culture in the above mentioned scaffolds.
Through our different models and experimental setups, we aim to address the various components involved in the complex MSC-microenvironment interaction in order to understand in which extend each of them can influence bone homeostasis and/or regeneration. Our model systems, closely mimicking the bone extracellular matrix environment, are also applied in collaborative research projects with the aim to decipher mechanisms in formation of bone metastasis by various tumors.
Bone marrow stromal cells in multiple myeloma
Multiple myeloma is an incurable hematologic malignancy and the bone marrow microenvironment plays a key role in myelomagenesis, neoplastic cell survival and drug resistance. Current approaches to personalize myeloma therapy do not consider the significance of the non-malignant surrounding for defining predictive and prognostic biomarkers to identify the likelihood of response to therapy, disease relapse and/or predict overall survival. In this project, we aim to investigate fundamental insights into drug-regulated malignant and normal stem/progenitor cells (BMSCs), elucidating novel critical points and targets in multiple myeloma therapy. The PhD project “Interplay between senescence and stem cell properties in multiple myeloma and mesenchymal stem cells - implications for therapy and diagnostics”, is supported by Bayerische Forschungsstiftung and associated to the “Tumordiagnostik für individualisierte Therapie (FORTiTher)” consortium.
The project is focused on three main subtopics: 1) Stemness regulation during BMSC and myeloma cell interactions, 2) Drug response and detoxification activity (cellular homeostasis) mechanisms of myeloma cells and 3) Senescence dynamics in BMSC and myeloma cells communication.
Phenotypic alteration in MSC derived from the peridontal ligament in hypophosphatasia
Hypophosphatasia (HPP) is a rare inherited disorder caused by loss-of-function mutations in the ALPL gene encoding the Tissue Nonspecific Alkaline Phosphatase (TNAP). Besides skeletal symptoms, some patients also present dental abnormalities like for example the premature loss of deciduous teeth. Knowledge of the underlying mechanisms for those symptoms are still limited. Therefore, this project focuses on the generation of TNAP-deficient cell lines with moderate to severe mutations applying CRISPR-Cas9 gene editing. A MSC cell line derived from the periodontal ligament was used to create a link to the dental symptoms in HPP patients. The newly generated cell lines are then compared with each other and a not-mutated wildtype control regarding their TNAP activity, mineralization characteristics and potential to undergo osteogenic differentiation. In future projects, the effects of parathormone stimulation on TNAP deficient cells will be investigated.