The musculoskeletal system as a clinical and scientific field of action
Diseases of the musculoskeletal system have the highest socio-economic relevance. Today around 80% of the population suffer from neck, shoulder or back pain in the course of their life. This statement will become even more explosive in the future due to increasing life expectancy. Innovative treatment approaches are necessary in order to enable optimal therapeutic success in the future with the shortest possible reconvalescence phase and the result of a long-term, full functional recovery. Regenerative medicine promises such innovative solutions. In particular, the successes in stem cell research (Nobel Prize 2012) provide additional momentum for this. The body’s own stem cells, amongst other sources of stem cells, are available for research and, if necessary, for clinical use. Further successes will result from the future optimization of biomedical implants. Here we focus in particular on the further refinement of musculoskeletal implants. The work of the group is located at the interface between basic science and clinical translation, since we bring results from our research – e. g. on signalling pathways – into application-oriented solutions – e. g. within a DFG-funded research group, see below.
Contributions to the MHH research focus “Transplantation, Regeneration”
In the skeletal system, the body’s own stem cells are the mesenchymal stromal / stem cells (MSCs). In addition to the hematopoietic stem cells, they form the second important group of tissue-specific stem cells and, like these, they are found in the bone marrow, but also in various other tissues of the body and in tissues associated with birth. In vivo and in vivo they can be differentiated into cells of the mesenchymal lineage: into bone, cartilage, tendon and ligament, fat or muscle cells. In addition, MSCs are immuno-privileged and have immunomodulatory (especially immunosuppressive) functions. These properties are mainly based on the effects of soluble factors released by MSCs. MSCs are therefore highly relevant from a medical point of view: next to the hematopoietic stem cells, they are most frequently used in clinical studies and for very different diseases, including rejection reactions (“graft versus host disease”) and autoimmune diseases, while applications in the skeletal system affect less than a quarter of all clinical studies.
MSCs thus represent a highly attractive cell source, both in terms of basic science and in application in biomedical research and technology. The work of my group contributes to unravel the importance of these cells for the areas of application mentioned and to make the results obtained in research and clinic more meaningful, reproducible and predictable in the future. To this end, we examine the function of human mesenchymal stem cells under normal and inflammatory conditions and develop novel isolation and cultivation strategies. The main focus is on the understanding of stem cell functions and networks of signal molecules. Last year, the RENEW-MSC working group of the MHH was able to publish the scientific results of a joint research work in a renowned specialist journal, “Cytotherapy”, and conjointly offers a lecture series to students.
Signaling Pathways in Regeneration: A Molecular Mechanism for Tendon Cell Formation. Genetically modified MSCs differentiated in vitro into tendon-like cells. A cell-mediated gene therapy of a segmental Achilles tendon defect in rats was made possible by implantation of the genetically modified cells in vivo. After intramuscular implantation, ectopic tendon formation took place or even tendon-bone transitions (osteotendinous junctions, entheses) were formed. This work laid the central basis for today’s funding in the DFG research group 2180 “Graduated Implants for Tendon-Bone Connections”, see chapter “Graded Implants”.
Signaling pathways in inflammation: TAK1 is involved in the development of rheumatoid arthritis. The MAP3 kinase TAK1 (Transforming Growth Factor-Activated Kinase 1) is a member of the mitogen-activated protein kinase family. It has integrative functions in the transmission of signals of TGF-beta family growth factors as well as in infections and inflammatory reactions. Scientists could show that TAK1 is involved in the development of fibrosis and influences the differentiation of tissue-permanent stem cells and immune cells. Rheumatoid arthritis is a chronic inflammatory disease that leads to progressive joint destruction. Although new biotherapies have revolutionized treatment, they often have side effects that make the further development of alternative anti-inflammatory strategies necessary. In a mouse model (collagen-induced arthritis in DBA/1 mice) we were able to show that the systemic inhibition of TAK1 led to a remission of the symptoms. This finding could enable the development of anti-inflammatory strategies as an alternative to existing biotherapies.
Contributions to the MHH research focus “Biomedical engineering, implants”
Graded implants. Biomedical implant research has so far concentrated on implants for homogeneously structured tissue types, e. g. bones. Implants for areas between tissues with very different properties have been researched less well. Natural tissue transitions have multiple gradients: gradients of the structure, the composition and the resulting functionality. Such tissue transitions play a special role in the field of orthopedics. Their functionality is frequently impaired by pathological processes. Ongoing treatment costs, revision operations and nonetheless unsatisfactory clinical results represent a considerable problem. As a representative example, the DFG-funded research group FOR 2180 “Graded implants for tendon-bone junctions” addresses the shoulder: www.gradierte-implantate.en. The aim is to establish the basic feasibility and model production of a novel biodegradable and multi-graded implant for future use at the tendon-bone junction of the rotator cuff. The FOR 2180 includes specialist areas from engineering, nature and life sciences and medicine. Three Lower Saxony universities – MHH, Leibniz University and Technical University of Braunschweig – are involved. The working group leader is the spokeswoman for this joint project.
Interaction between biomaterials and the immune system. Current results of the FOR 2180 show a massive foreign body reaction and fibrosis. We believe that the effects of inflammation and immune responses should be given greater consideration in future developments in regenerative therapies, including biomaterials and implants. For example, anti-inflammatory and immunomodulatory approaches could in many cases sustainably promote or even enable successful regeneration, including the potentiation of stem cell and growth factor effects. In the future, we would like to develop tailor-made strategies for this and characterize specific immune cell populations.
Contributions to the MHH research focus “Oncology”
Alteration of MSCs by sarcomas. In recent years we have received some bone marrow samples from patients diagnosed with sarcoma from the orthopedic clinic. From this material, we isolated MSCs and characterized their RNA profile. Changes could be deciphered which distinguish cells of patients with and patients without a tumor diagnosis from each other. In addition, each sarcoma entity may present specific changes. In the future, we would like to functionally characterize selected genes and extend the analysis to additional cell populations as well.
Selected publications from the last 5 years (bold type: employees AG Hoffmann)
*: equivalent contributions, #: correspondence
Friese, N., Gierschner, M.B., Schadzek, P., Roger, Y., Hoffmann, A. (2020):
Regeneration of Damaged Tendon-Bone Junctions (Entheses): TAK1 as a Potential Node Factor.
Int J Mol Sci;21:E5177.
Lavrentieva, A.*, Hoffmann, A.*, Lee-Thedieck, C.* (2020):
Limited Potential or Unfavorable Manipulations? Strategies Toward Efficient Mesenchymal Stem/Stromal Cell-Applications.
Front Cell Dev Biol;8:316
Roger, Y., Sydow, S., Burmeister, L., Menzel, H., Hoffmann, A.# (2020):
Sustained release of TGF-β3 from polysaccharide nanoparticles induces chondrogenic differentiation of human mesenchymal stromal cells.
Colloids Surf B Biointerfaces;189:110843
Roger, Y., Burmeister, L., Hamm, A., Elger, K., Dittrich-Breiholz, O., Flörkemeier, T.*, Hoffmann, A.* # (2020):
Heparin Anticoagulant for Human Bone Marrow Does Not Influence In Vitro Performance of Human Mesenchymal Stromal Cells.
Winkel, A., Jaimes, Y., Melzer, C., Dillschneider, P., Hartwig, H., Stiesch, M., von der Ohe, J., Strauss, S., Vogt, P.M., Hamm, A., Burmeister, L., Roger, Y., Elger, K., Flörkemeier, T., Weissinger, E.M., Pogozhykh, O., Müller, T., Selich, A., Rothe, M., Petri, S., Köhl, U., Hass, R., Hoffmann, A.# (2020):
Cell culture media notably influence properties of human mesenchymal stroma/stem-like cells from different tissues.
Gniesmer, S., Brehm, R., Hoffmann, A., de Cassan, D., Menzel, H., Hoheisel, A.-L., Glasmacher, B., Willbold, E., Reifenrath, J., Ludwig, N., Zimmerer, R., Tavassol, F., Gellrich, N.-C., Kampmann, A. (2020):
Vascularization and biocompatibility of poly(ε-caprolactone) fiber mats for rotator cuff tear repair.
Schwieger, J., Hamm, A., Gepp, M.M., Schulz, A., Hoffmann, A., Lenarz, T., Scheper, V. (2020):
Alginate-encapsulated Brain Derived Neurotrophic Factor-overexpressing mesenchymal stem cells are a promising drug delivery system for protection of auditory neurons.
J Tissue Eng.;11:1-15
De Cassan, D., Becker, A., Glasmacher, B., Roger, Y., Hoffmann, A., Gengenbach, T.R., Easton, C. D., Hänsch, R., Menzel, H. (2020):
Blending chitosan-g-poly(caprolactone) with poly(caprolactone) by electrospinning to produce functional fiber mats for tissue engineering applications.
J Appl Polym Sci; DOI: 10.1002/APP.48650
Willbold, E.; Wellmann, M. Welke, B., Angrisani, N., Gniesmer, S., Kampmann, A., Hoffmann, A., De Cassan, D., Menzel, H., Hoheisel, A.-L., Glasmacher, B., Reifenrath, J. (2020):
Possibilities and limitations of electrospun chitosan-coated polycaprolactone grafts for rotator cuff tear repair
J Tissue Eng Regen Med;14(1):186-197
Scheper, V., Schwieger, J., Hamm, A., Lenarz, T., Hoffmann, A. (2019):
BDNF-overexpressing human mesenchymal stem cells mediate increased neuronal protection in vitro.
J Neurosci Res;97(11):1414-1429
Weist, R., Flörkemeier, T., Roger, Y., Noack, S., Franke, A., Schwanke, K., Zweigerdt, R., Martin, U., Willbold E.*, Hoffmann, A.* # (2018):
Differential expression of cholinergic system components in human induced pluripotent stem cells, bone marrow-derived multipotent stromal cells, and induced pluripotent stem cell-derived multipotent stromal cells.
Stem Cells Dev;27;166-183
Hoffmann, A., Floerkemeier, T., Melzer, C., Hass, R. (2017):
Comparison of in vitro-cultivation of human mesenchymal stroma/stem cells derived from bone marrow and umbilical cord.
J Tissue Eng Regen Med; 11(9):2565-2581
Prof. Dr. Andrea Hoffmann: spokeswoman for DFG-FOR 2180, member of the scientific advisory board of the “Rostock Center for Interdisciplinary Implant Research” ROCINI, member of AcademiaNet.
“Adult stem cells in regenerative medicine” (lecture)
“Development of cell therapeutics: Experimental applications and clinical use of adult stem cells” (lecture series)
“Introduction to animal cell culture technology” (lab course at NIFE)
Teaching Award 2021 to Prof. Dr. Andrea Hoffmann