Project

Discipline

stem cells; muscle; positron emission tomography; PGC-1alpha; muscle precursor cells; tissue engineering

Lead
Lay summary
The ability to regenerate muscle tissue using the patients own stem cells would have profound impact on many human diseases. Unfortunately, the decreased capacity and growth of such muscle precursor cells (MPCs) in elderly individuals or patients suffering from many muscle diseases hinder efficient clinical application of such a stem cell-based therapy. We aim at improving the outcome of autologous stem cell treatment in skeletal muscle by using engineered MPCs with increased expression of PGC-1alpha, a key factor in the regulation of endurance exercise adaptation in skeletal muscle. Moreover, we plan to establish new positron emission tomography (PET)-based methods to monitor the fate, the integration and the function of the injected muscle precursor cells in vivo in a longitudinal, non-invasive manner. PET using radioactively labeled molecules is a highly sensitive, quantiative imaging modality, which provides information on functional physiological and biochemical changes and is widely used in cancer diagnostics and other fields in the clinic. We hope that our projects contributes to the understanding and further advancement of autologous stem cell therapy in the treatment of muscle diseases.

Direct link to Lay Summary

Last update: 21.02.2013

Active participation

Communication	Title	Media	Place	Year

Number	Title	Start	Funding scheme

Improving human muscle engineering by PGC-1alpha expression and molecular imaging using positron emission tomography (PET)Christoph Handschin, Biozentrum, University of Basel (Subproject A)Daniel Eberli, University Hospital Zurich (Subproject B)Simon Ametamey, ETH Zurich (Subproject C)Summary of the research planThe ability to regenerate muscle tissue from patients own cells would have profound impact on many human diseases. Cell therapy is within reach as a novel treatment option for incontinence, reflux, vocal cord dysfunction and other muscle-related pathologies. Muscle precursor cells (MPCs) are quiescent adult stem cells and are located under the membrane surrounding the muscle fibers. After trauma or damage, MPCs participate in tissue regeneration by proliferating and differentiating into myoblasts and later fuse to form new myofibers. The majority of MPCs is committed to the myogenic lineage and MPCs are therefore most suitable for muscle engineering.Despite the progress in the field of muscle tissue engineering, one of the main problems is the decreased capacity and growth of MPCs in the aged population since many clinical conditions for which muscle tissue engineering will be useful are commonly found in the elderly patients. Importantly, even in these individuals, the ability of MPCs to regenerate muscle fibers can be improved by exercise and therapeutic regulation of gene expression.The transcriptional coactivator peroxisome proliferator-activated receptor ? coactivator 1a (PGC-1a) is a key integrator of neuromuscular activity in skeletal muscle and plays an important role in exercise-mediated adaptations. PGC-1a expression is regulated proportionally to the amount of exercise in a muscle and protects skeletal muscle from atrophy. PGC-1a is also involved in the muscle fiber-type switch towards oxidative muscle fibers that are capable to sustain long-term contractions.Many different cellular therapies are on the door step into clinics. Therefore, a method to track transplanted cells and to determine the functional outcome of these interventions in a non-invasive manner is of key interest. Specifically, the ability to monitor these cells in “real time” would allow us to better understand tissue reconstruction and effectiveness of the cell-based therapies elucidate homing process, distribution, local retention and functional integration of transplanted stem cells in vivo. Positron Emission Tomography (PET) using radioactively labeled molecules is a highly sensitive, quantitative imaging modality which provides information on functional physiologic or biochemical changes in vivo. We hypothesize that human MPCs supplemented with PGC-1a are able to form new functional muscle tissue with improved functional properties. Our project thus aims at the generation and validation of viral vectors for ectopic expression of PGC-1a in MPCs, assess the therapeutic potential of these engineered MPCs in two mouse models in vivo, longitudinally track these injected mouse muscle precursors non-invasively with PET. In the past, while most effort was put on reporter system development and evaluation in the past, less attention was paid to the possibility of PET monitoring of the functionality of the engineered tissues. Besides using the dopamine D2 receptor as a reporter gene, we will follow features such as glucose metabolic state, oxygenation status, VEGF release and/ or the vascularisation level of the transplanted MPCs over time with established PET tracers with the aim to finally establish new PET-based protocols to non-invasively assess the therapeutic efficacy of the cellular treatment. The PET analysis will be combined with a thorough functional characterization of engineered MPCs in culture in order to define cellular parameters that are predictive for a high therapeutic efficacy in subsequent application in vivo. Hopefully, these data will provide insights into novel approaches to overcome the limitations of autologous stem cell treatment of single muscles in elderly patients.