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Improving human muscle engineering by PGC-1alpha expression and molecular imaging using positron emission tomography (PET)

Applicant Handschin Christoph
Number 136197
Funding scheme Sinergia
Research institution Biozentrum der Universität Basel Systembiologie
Institution of higher education University of Basel - BS
Main discipline Biomedical Engineering
Start/End 01.01.2012 - 31.12.2014
Approved amount 1'100'000.00
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All Disciplines (4)

Discipline
Biomedical Engineering
Cellular Biology, Cytology
Molecular Biology
Surgery

Keywords (6)

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

Lay Summary (English)

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

Responsible applicant and co-applicants

Employees

Publications

Publication
Non-Invasive Tracking of Muscle Precursor Cells for Sphincter Muscle Engineering
Haralampieva D., Salemi S., Betzel T., Dinulovic I., Kraemer S., Sulser T., Handschin C., Ametamey S., Eberli D. (2014), Non-Invasive Tracking of Muscle Precursor Cells for Sphincter Muscle Engineering, in TISSUE ENGINEERING PART A, 20, 68-68.
Myoblasts inhibit prostate cancer growth by paracrine secretion of TNF alpha.
Stölting Meline N L, Ferrari Stefano, Handschin Christoph, Becskei Attila, Provenzano Maurizio, Sulser Tullio, Eberli Daniel (2013), Myoblasts inhibit prostate cancer growth by paracrine secretion of TNF alpha., in The Journal of urology, 189(5), 1952-1959.
In vivo electromagnetic stimulation supports muscle regeneration after stem cell injection by boosting muscular metabolism and stimulating nerve ingrowth
Stoelting M. N. L., Handschin C., Becskei A., Sulser T., Eberli D. (2012), In vivo electromagnetic stimulation supports muscle regeneration after stem cell injection by boosting muscular metabolism and stimulating nerve ingrowth, in JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, 6, 26-26.
Noninvasive electromagnetic stimulation for stress urinary incontinence improves regeneration of skeletal muscle, increases nerve ingrowth and acetylcholine receptor clustering
Stoelting M. N. L., Handschin C., Becskei A., Sulser T., Eberli D. (2012), Noninvasive electromagnetic stimulation for stress urinary incontinence improves regeneration of skeletal muscle, increases nerve ingrowth and acetylcholine receptor clustering, in EUROPEAN UROLOGY SUPPLEMENTS, 11(1), 1064-221.
External physical and biochemical stimulation to enhance skeletal muscle bioengineering
Handschin Christoph, Mortezavi Ashkan, Plock Jan, Eberli Daniel, External physical and biochemical stimulation to enhance skeletal muscle bioengineering, in Adv Drug Deliv Rev, epub ahead of print.

Collaboration

Group / person Country
Types of collaboration
PD Dr. C. Maake / Institute of Anatomy _ University Hospital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
PD Dr. H. Hall / Biomaterials / ETH ZH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. A. Atala/ Institute of Regenerative Medicine- Wake Forest University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Sanjiv S. Gambhir/University of Stanford United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dr. G. Courtine / Neuro / Uni ZH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. L. Scapozza/University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Bruce M. Spiegelman / Dana-Farber Cancer Institute and Harvard Medical School United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
TERMIS-AM Meeting 2014 Talk given at a conference Non-invasive Tracking of Muscle Precursor Cells for Muscle Tissue Engineering Using PET 13.12.2014 Washington DC, United States of America Eberli Daniel; Salemi Souzan; Stölting Meline Nogueira Lucena;
EMBO Workshop: Molecular Biology of Muscle Development and Regeneration Poster PGC-1alpha in muscle regeneration 14.05.2014 Lecce, Italy Svensson Kristoffer;
TERMIS-AP conference 2013 Poster Non-Invasive Tracking Of Muscle Precursor Cells For Muscle Tissue Engineering 23.10.2013 Shanghai, China Handschin Christoph; Eberli Daniel; Ametamey Simon M.; Betzel Thomas;
9th Symposium of the ZIHP, University of Zurich Poster Non-invasive tracking of muscle precursor cells for muscle tissue engineering 23.08.2013 Zurich, Switzerland Eberli Daniel;
12th clinical research day 2013, University of Zurich Poster Volume limitations in cell therapy for muscle engineering 04.04.2013 Zurich, Switzerland Eberli Daniel;
Austrian Cluster for Tissue Regeneration Talk given at a conference Non-invasive tracking of muscle precursor cells for muscle tissue engineering 17.10.2012 Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Wien, Austria Eberli Daniel;
59th Annual Meeting of the American College of Sports Medicine (ACSM) Talk given at a conference Transcriptional Regulation of Skeletal Muscle Cell Plasticity in Health and Disease 30.05.2012 San Francisco, USA, United States of America Handschin Christoph;


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Laborbesuch Gymnasium Münchenstein German-speaking Switzerland 2012

Associated projects

Number Title Start Funding scheme
145005 Mitochondrial function in metabolism and inflammation 01.01.2013 R'EQUIP
156654 Immunometabolism in skeletal muscle plasticity and cancer cachexia 01.01.2015 Project funding
110746 Molecular mechanisms regulating skeletal muscle plasticity 01.12.2006 SNSF Professorships
126230 Muscle Precursor Cells for the treatment of Urinary Incontinence 01.10.2009 Ambizione
126963 Development of PET reporter probes with improved sensitivity and specificity for in vivo monitoring of gene and cell-based therapy using HSV1-tk as a reporter gene 01.10.2009 Project funding
144935 Muscle Precursor Cells for the treatment of Urinary Incontinence 01.10.2012 Ambizione
157763 MobiPET: A mobile, small animal PET scanner for molecular imaging 01.03.2015 R'EQUIP

Abstract

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.
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