The research group "Cell Biology" investigates the biology of adult stem cells, immune cells, endothelial precursors and fibroblasts as well as their possible role in musculoskeletal tissue regeneration. We are looking at the interaction between cells, mechanics and the extracellular matrix. Furthermore, we are concentrating on alterations of intrinsic cell functions in response to extrinsic stimuli, such as age or an altered immune response. Our long-term goal is to develop new therapeutic approaches to improve musculoskeletal tissue regeneration, especially for impaired healing cases.
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The process of endogenous bone fracture repair restores prefractured properties and functions under optimal conditions. However, under certain constraints such as severe trauma, enhanced age, steroid therapy, or diabetes, this process can be delayed and may even result in incomplete healing and poor long-term outcome. About 5 to 15% of patients suffer from such complications after a fracture. These patients require additional surgery, which is associated with prolonged hospitalization and rehabilitation time and results in a high socioeconomic impact.
Currently, no reliable methods exist to prospectively identify patients at risk of impaired fracture healing. This may be a result of the wide interindividual variability in the degree of the injury, the associated soft tissue trauma, the patient’s compliance, the differences in anatomical reconstruction, and the inflammatory response at the onset of healing.
In addition to mesenchymal cells, immune cells are crucial for the endogenous regeneration of mesenchymal tissues even in the absence of infection. We previously found a relation between individual’s immune reactivity, the function of bone precursor cells (Mesenchymal Stromal Cells, MSCs) and disturbed fracture healing in humans. Our study revealed that compromised fracture healing is significantly correlated with enhanced levels of circulating terminally differentiated CD8+ effector memory T (TEMRA) cells. These cells were enriched in the hematoma and are major producers of TNF-α and IFN-γ, which inhibit osteogenic differentiation and survival of human MSCs (Fig.). To further investigate a causal relation between the enrichment of TEMRA cells, compromised MSC function, and the pathogenesis of poor bone fracture healing, we specifically depleted CD8+ T-cells in vivo by an antibody therapy. This treatment resulted in an enhanced endogenous fracture repair, whereas a transfer of CD8+ T-cells impaired the healing process. Our current data are the foundation of two ongoing studies (i) prospective validation of the biomarker CD8+ TEMRA cells in a large clinical (multi-center) trial, and (ii) the pharmacologically blocking the circulating CD8+ TEMRA cells or their cytokines to enhance fracture healing.
- Authors:Schlundt C, Fischer H, Bucher CH, Rendenbach C, Duda GN, Schmidt-Bleek K
Journal:Acta Biomater Year:2021;
Title:The multifaceted roles of macrophages in bone regeneration: A story of polarization, activation and time
- Authors:Knecht RS, Bucher CH, Van Linthout S, Tschöpe C, Schmidt-Bleek K, Duda GN
Journal:Front Bioeng Biotechnol Year:2021; Volume:9
Title:Mechanobiological Principles Influence the Immune Response in Regeneration: Implications for Bone Healing
- Authors:Garbe A, Graef F, Appelt J, Schmidt-Bleek K, Jahn D, Lünnemann T, Tsitsilonis S, Seemann R
Journal:Int J Mol Sci Year:2020; Volume:21Issue:(23)
Title:Leptin Mediated Pathways Stabilize Posttraumatic Insulin and Osteocalcin Patterns after Long Bone Fracture and Concomitant Traumatic Brain Injury and Thus Influence Fracture Healing in a Combined Murine Trauma Model
- Authors:Berkmann JC, Herrera Martin AX, Pontremoli C, Zheng K, Bucher CH, Ellinghaus A, Boccaccini AR, Fiorilli S, Brovarone CV, Duda GN, Schmidt-Bleek K
Journal:Pharmaceutics Year:2020; Volume:12Issue:(9)
Title:In Vivo Validation of Spray-Dried Mesoporous Bioactive Glass Microspheres Acting as Prolonged Local Release Systems for BMP-2 to Support Bone Regeneration
- Authors:Boffito M, Torchio A, Tonda-Turo C, Laurano R, Gisbert-Garzarán M, Berkmann JC, Cassino C, Manzano M, Duda GN, Vallet-Regí M, Schmidt-Bleek K, Ciardelli G
Journal:Front Bioeng Biotechnol Year:2020; Volume:8:Pages:384.
Title:Hybrid Injectable Sol-Gel Systems Based on Thermo-Sensitive Polyurethane Hydrogels Carrying pH-Sensitive Mesoporous Silica Nanoparticles for the Controlled and Triggered Release of Therapeutic Agents
- Authors:Eder CH, Schmidt-Bleek K, Geissler S, Sass FA, Maleitzke T, Pumberger M, Perka C, Duda GN, Winkler T
Journal:Mol Biol Rep Year:2020;
Title:Mesenchymal Stromal Cell and Bone Marrow Concentrate Therapies for Musculoskeletal Indications: A Concise Review of Current Literature
- Authors:Berkmann JC, Herrera Martin AX, Ellinghaus A, Schlundt C, Schell H, Lippens E, Duda GN, Tsitsilonis S, Schmidt-Bleek K
Journal:Int J Mol Sci Year:2020; Volume:21Issue:(7)
Title:Early pH Changes in Musculoskeletal Tissues upon Injury-Aerobic Catabolic Pathway Activity Linked to Inter-Individual Differences in Local pH
- Authors:Gisbert-Garzarán M, Berkmann JC, Giasafaki D, Lozano D, Spyrou K, Manzano M, Steriotis T, Duda GN, Schmidt-Bleek K, Charalambopoulou G, Vallet-Regí MJournal:ACS Appl Mater Interfaces Year:2020;
- Authors:Garske DS, Schmidt-Bleek K, Ellinghaus A, Dienelt A, Gu L, Mooney DJ, Duda G, Cipitria A
Journal:Tissue Eng Part A Year:2020;
Title:Alginate Hydrogels for In Vivo Bone Regeneration: The Immune Competence of the Animal Model Matters
- Authors:Stefanowski J, Lang A, Rauch A, Aulich L, Köhler M, Fiedler AF, Buttgereit F, Schmidt-Bleek K, Duda GN, Gaber T, Niesner RA Hauser AE1,2.
Journal:Front Immunol Year:2019; Volume:10
Title:Spatial Distribution of Macrophages During Callus Formation and Maturation Reveals Close Crosstalk Between Macrophages and Newly Forming Vessels