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Mechanisms of improved functional recovery after skeletal muscle trauma through the transplantation of mesenchymal stem cells: Investigation of the paracrine factors of MSC and the local environment

Prof. Duda  (first supervisor), Prof. Perka (second supervisor), Dr. Winkler (mentor); Charité

Skeletal muscle trauma leads to severe functional deficits. Present therapeutic treatments are unsatisfying and insufficient posttraumatic regeneration is a problem in trauma and orthopaedic surgery. The transplantation of progenitor cells provides a promising new approach to address this problem and has already been translated from bench to bedside for the regeneration of heart muscle. Initial studies of our group showed that the local transplantation of bone marrow derived mesenchymal stem cells (MSC) after skeletal muscle trauma results in a significant improvement of contraction force after a severe crush injury of the rat soleus muscle. In addition we demonstrated a doseresponse relationship of the amount of injected MSC and force enhancement. We furthermore investigated the fate of the transplanted MSC labelled with very small iron oxide particles using 7 Tesla-MRI. Histological analyses revealed fusion events between existing myofibers but only to a low amount. The increase of muscle force can not be explained by these events only. The goal of the intended project is to investigate the mechanisms how the transplanted MSC contribute to improved functional recovery. It is planned to investigate how the local environment of the muscle changes after trauma in time, which factors have an impact on MSC, how the cells respond to this trigger and which factors are secreted by them. A successful termination of the trials will reveal significant knowledge about the mode of action of MSC on regeneration of skeletal muscle. Before further steps are taken into clinical application of MSC for the treatment of muscular injuries, the understanding of these mechanisms is essential.

References
Matziolis G, Winkler T. et al. (2006). Autologous bone marrow-derived cells enhance muscle strength following skeletal muscle crush injury in rats. Tissue Eng 12(2): 361-7. Winkler T, von Roth P. et al. (2008). In vivo visualization of locally transplanted mesenchymal stem cells in the severely injured muscle in rats. Tissue Eng Part A 14(7): 1149-60.

Winkler, T., P. von Roth, et al. (2009). Dose-Response Relationship of Mesenchymal Stem Cell Transplantation and Functional Regeneration after Severe Skeletal Muscle Injury in Rats. Tissue Eng Part A.