Cell Biology

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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Prognostic Biomarkers

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.

CD8+ TEMRA cells accumulates in the fracture hematoma and are locally the major of pro-inflammatory cytokines. The healing process of long bone fracture is usually divided into different phases. Beginning with a pro-inflammatory response and an initial hematoma formation, subsequently new blood vessels grow into the fracture area and fibrocartilaginous callus followed by a bony callus will be formed. During this final remodeling phase, the original bone structure will be restored. The pro-inflammatory CD8+ TEMRA cells are thought to inhibit this process. These cells were recruited from the peripheral blood into the hematoma and are locally the major producer of interferon-γ and tumor necrosis factor–α (orange dots), which inhibit the differentiation of MSCs (green) and induce their apoptosis (dark purple).
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Dr. rer. medic. Simon Reinke

Core Facility Scientist

Publications

Durek P, Nordström K, Gasparoni G, Salhab A, Kressler C, de Almeida M, Bassler K, Ulas T, Schmidt F, Xiong J, Glažar P, Klironomos F, Sinha A, Kinkley S, Yang X, Arrigoni L, Amirabad AD, Ardakani FB, Feuerbach L, Gorka O, Ebert P, Müller F, Li N, Frischbutter S, Schlickeiser S, Cendon C, Fröhler S, Felder B, Gasparoni N, Imbusch CD, Hutter B, Zipprich G, Tauchmann Y, Reinke S, Wassilew G, Hoffmann U, Richter AS, Sieverling L; DEEP Consortium., Chang HD, Syrbe U, Kalus U, Eils J, Brors B, Manke T, Ruland J, Lengauer T, Rajewsky N, Chen W, Dong J, Sawitzki B, Chung HR, Rosenstiel P, Schulz MH, Schultze JL, Radbruch A, Walter J, Hamann A, Polansky JK.
Epigenomic Profiling of Human CD4+ T Cells Supports a Linear Differentiation Model and Highlights Molecular Regulators of Memory Development.
Immunity. 2016 Nov 15;45(5):1148-1161. doi: 10.1016/j.immuni.2016.10.022.

Sass FA, Schmidt-Bleek K, Ellinghaus A, Filter S, Rose A, Preininger B, Reinke S, Geissler S, Volk HD, Duda GN, Dienelt A.
CD31+ Cells From Peripheral Blood Facilitate Bone Regeneration in Biologically Impaired Conditions Through Combined Effects on Immunomodulation and Angiogenesis.
J Bone Miner Res. 2016 Dec 15. doi: 10.1002/jbmr.3062. [Epub ahead of print]

Pumberger M, Qazi TH, Ehrentraut MC, Textor M, Kueper J, Stoltenburg-Didinger G, Winkler T, von Roth P, Reinke S, Borselli C, Perka C, Mooney DJ, Duda GN, Geißler S.
Synthetic niche to modulate regenerative potential of MSCs and enhance skeletal muscle regeneration.
Biomaterials. 2016 Aug;99:95-108. doi: 10.1016/j.biomaterials.2016.05.009. Epub 2016 May 10.

Okhrimenko A, Grün JR, Westendorf K, Fang Z, Reinke S, von Roth P, Wassilew G, Kühl AA, Kudernatsch R, Demski S, Scheibenbogen C, Tokoyoda K, McGrath MA, Raftery MJ, Schönrich G, Serra A, Chang HD, Radbruch A, Dong J.
Human memory T cells from the bone marrow are resting and maintain long-lasting systemic memory.
Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9229-34. doi: 10.1073/pnas.1318731111. Epub 2014 Jun 10.

Reinke S, Dienelt A, Blankenstein A, Duda GN, Geissler S.
Qualifying stem cell sources: how to overcome potential pitfalls in regenerative medicine?
J Tissue Eng Regen Med. 2016 Jan;10(1):3-10. doi: 10.1002/term.1923. Epub 2014 Jun 12. Review

Reinke S, Geissler S, Taylor WR, Schmidt-Bleek K, Juelke K, Schwachmeyer V, Dahne M, Hartwig T, Akyüz L, Meisel C, Unterwalder N, Singh NB, Reinke P, Haas NP, Volk HD, Duda GN.
Terminally differentiated CD8⁺ T cells negatively affect bone regeneration in humans.
Sci Transl Med. 2013 Mar 20;5(177):177ra36. doi: 10.1126/scitranslmed.3004754. Erratum in: Sci Transl Med. 2013 May 29;5(187):187er4.

Reinke S, Karhausen T, Doehner W, Taylor W, Hottenrott K, Duda GN, Reinke P, Volk HD, Anker SD.
The influence of recovery and training phases on body composition, peripheral vascular function and immune system of professional soccer players.
PLoS One. 2009;4(3):e4910. doi: 10.1371/journal.pone.0004910. Epub 2009 Mar 18.

Reinke S, Taylor WR, Duda GN, von Haehling S, Reinke P, Volk HD, Anker SD, Doehner W.
Absolute and functional iron deficiency in professional athletes during training and recovery.
Int J Cardiol. 2012 Apr 19;156(2):186-91. doi: 10.1016/j.ijcard.2010.10.139. Epub 2010 Dec 9.