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Project

Characterization and functional phenotyping of the immune component of the bone fracture niche.

Fractures of the long bones are the most common large organ trauma worldwide (Einhorn & Gerstenfeld, Nature Reviews Rheumatology, 2015; Ho-shui-Ling et al., Biomaterials, 2018). In about 5% of all cases the broken bone fails to heal, resulting in a so-called non-union defect. The underlying causes are highly variable, ranging from genetic defects, disease, comorbidities at the defect site or lifestyle choices such as smoking or alcohol consumption. Commonly, this leads to poor vascularization and a lack of potent progenitor cells required to regenerate the bone at the defect site. There currently is still no reliable treatment strategy available for these patients and several tissue engineering (TE) approaches are currently under development. One of the hallmarks of bone injury is the induction of an acute and tightly regulated inflammatory response that is not only beneficial, but also required for healing (Gerstenfeld et al., Cells Tissues Organs, 2001; Gerstenfeld et al., JBMR, 2003, Raggatt et al., Am J Pathol., 2014, Schmidt-Bleek et al., Cell Tissue Res., 2012). However, if this phase of the regeneration cascade goes awry due to persistence of pro-inflammatory stimuli, the defect site may enter a state of chronic inflammation. Characteristic for this unresolved inflammatory response is the continued secretion of cytokines and ongoing tissue destruction, which if left unchecked will result in a delay or failure of healing. Therefore, bone healing should be considered an osteo-immunological phenomenon (Arron & Choi, Nature, 2000). In this project we will execute a full characterization of the immune response in the early stages of fracture regeneration through the combined and integrated use of single-cell RNA sequencing and proteomics. To validate our findings, key cell subpopulations or -states will be ablated in loss-of-function experiments. Lastly, we will apply newfound insights in immune system-derived signaling molecules to better tailor TE constructs for implantation and improve graft incorporation.

Date:14 Sep 2021 →  Today
Keywords:Tissue engineering, Bone fracture, Developmental biology, Single-cell RNA sequencing
Disciplines:Tissue engineering, Developmental genetics, Analysis of next-generation sequence data, Genetics
Project type:PhD project