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Skeletal Muscle Differentiation on a Chip Shows Human Donor Mesoangioblasts' Efficiency in Restoring Dystrophin in a Duchenne Muscular Dystrophy Model.
Stem Cells Transl Med. 2016 12; 5(12):1676-1683.SC

Abstract

: Restoration of the protein dystrophin on muscle membrane is the goal of many research lines aimed at curing Duchenne muscular dystrophy (DMD). Results of ongoing preclinical and clinical trials suggest that partial restoration of dystrophin might be sufficient to significantly reduce muscle damage. Different myogenic progenitors are candidates for cell therapy of muscular dystrophies, but only satellite cells and pericytes have already entered clinical experimentation. This study aimed to provide in vitro quantitative evidence of the ability of mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from DMD patients, using a microengineered model. We designed an ad hoc experimental strategy to miniaturize on a chip the standard process of muscle regeneration independent of variables such as inflammation and fibrosis. It is based on the coculture, at different ratios, of human dystrophin-positive myogenic progenitors and dystrophin-negative myoblasts in a substrate with muscle-like physiological stiffness and cell micropatterns. Results showed that both healthy myoblasts and mesoangioblasts restored dystrophin expression in DMD myotubes. However, mesoangioblasts showed unexpected efficiency with respect to myoblasts in dystrophin production in terms of the amount of protein produced (40% vs. 15%) and length of the dystrophin membrane domain (210-240 µm vs. 40-70 µm). These results show that our microscaled in vitro model of human DMD skeletal muscle validated previous in vivo preclinical work and may be used to predict efficacy of new methods aimed at enhancing dystrophin accumulation and distribution before they are tested in vivo, reducing time, costs, and variability of clinical experimentation.

SIGNIFICANCE

This study aimed to provide in vitro quantitative evidence of the ability of human mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from patients with Duchenne muscular dystrophy (DMD), using a microengineered model. An ad hoc experimental strategy was designed to miniaturize on a chip the standard process of muscle regeneration independent of variables such as inflammation and fibrosis. This microscaled in vitro model, which validated previous in vivo preclinical work, revealed that mesoangioblasts showed unexpected efficiency as compared with myoblasts in dystrophin production. Consequently, this model may be used to predict efficacy of new drugs or therapies aimed at enhancing dystrophin accumulation and distribution before they are tested in vivo.

Authors+Show Affiliations

Industrial Engineering Department, University of Padova, Padova, Italy. Venetian Institute of Molecular Medicine, Padova, Italy.Industrial Engineering Department, University of Padova, Padova, Italy. Venetian Institute of Molecular Medicine, Padova, Italy.Industrial Engineering Department, University of Padova, Padova, Italy. Venetian Institute of Molecular Medicine, Padova, Italy.Industrial Engineering Department, University of Padova, Padova, Italy. Venetian Institute of Molecular Medicine, Padova, Italy.Department of Cell and Developmental Biology, University College London, London, United Kingdom.Institute of Inflammation and Repair Manchester, University of Manchester, Manchester, United Kingdom.Industrial Engineering Department, University of Padova, Padova, Italy nicola.elvassore@unipd.it giulio.cossu@manchester.ac.uk. Venetian Institute of Molecular Medicine, Padova, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27502519

Citation

Serena, Elena, et al. "Skeletal Muscle Differentiation On a Chip Shows Human Donor Mesoangioblasts' Efficiency in Restoring Dystrophin in a Duchenne Muscular Dystrophy Model." Stem Cells Translational Medicine, vol. 5, no. 12, 2016, pp. 1676-1683.
Serena E, Zatti S, Zoso A, et al. Skeletal Muscle Differentiation on a Chip Shows Human Donor Mesoangioblasts' Efficiency in Restoring Dystrophin in a Duchenne Muscular Dystrophy Model. Stem Cells Transl Med. 2016;5(12):1676-1683.
Serena, E., Zatti, S., Zoso, A., Lo Verso, F., Tedesco, F. S., Cossu, G., & Elvassore, N. (2016). Skeletal Muscle Differentiation on a Chip Shows Human Donor Mesoangioblasts' Efficiency in Restoring Dystrophin in a Duchenne Muscular Dystrophy Model. Stem Cells Translational Medicine, 5(12), 1676-1683.
Serena E, et al. Skeletal Muscle Differentiation On a Chip Shows Human Donor Mesoangioblasts' Efficiency in Restoring Dystrophin in a Duchenne Muscular Dystrophy Model. Stem Cells Transl Med. 2016;5(12):1676-1683. PubMed PMID: 27502519.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Skeletal Muscle Differentiation on a Chip Shows Human Donor Mesoangioblasts' Efficiency in Restoring Dystrophin in a Duchenne Muscular Dystrophy Model. AU - Serena,Elena, AU - Zatti,Susi, AU - Zoso,Alice, AU - Lo Verso,Francesca, AU - Tedesco,F Saverio, AU - Cossu,Giulio, AU - Elvassore,Nicola, Y1 - 2016/08/08/ PY - 2015/03/19/received PY - 2016/06/09/accepted PY - 2016/8/10/pubmed PY - 2017/6/2/medline PY - 2016/8/10/entrez KW - Cellular therapy KW - Muscular dystrophy KW - Pericytes KW - Technology KW - Tissue regeneration SP - 1676 EP - 1683 JF - Stem cells translational medicine JO - Stem Cells Transl Med VL - 5 IS - 12 N2 - : : Restoration of the protein dystrophin on muscle membrane is the goal of many research lines aimed at curing Duchenne muscular dystrophy (DMD). Results of ongoing preclinical and clinical trials suggest that partial restoration of dystrophin might be sufficient to significantly reduce muscle damage. Different myogenic progenitors are candidates for cell therapy of muscular dystrophies, but only satellite cells and pericytes have already entered clinical experimentation. This study aimed to provide in vitro quantitative evidence of the ability of mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from DMD patients, using a microengineered model. We designed an ad hoc experimental strategy to miniaturize on a chip the standard process of muscle regeneration independent of variables such as inflammation and fibrosis. It is based on the coculture, at different ratios, of human dystrophin-positive myogenic progenitors and dystrophin-negative myoblasts in a substrate with muscle-like physiological stiffness and cell micropatterns. Results showed that both healthy myoblasts and mesoangioblasts restored dystrophin expression in DMD myotubes. However, mesoangioblasts showed unexpected efficiency with respect to myoblasts in dystrophin production in terms of the amount of protein produced (40% vs. 15%) and length of the dystrophin membrane domain (210-240 µm vs. 40-70 µm). These results show that our microscaled in vitro model of human DMD skeletal muscle validated previous in vivo preclinical work and may be used to predict efficacy of new methods aimed at enhancing dystrophin accumulation and distribution before they are tested in vivo, reducing time, costs, and variability of clinical experimentation. SIGNIFICANCE: This study aimed to provide in vitro quantitative evidence of the ability of human mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from patients with Duchenne muscular dystrophy (DMD), using a microengineered model. An ad hoc experimental strategy was designed to miniaturize on a chip the standard process of muscle regeneration independent of variables such as inflammation and fibrosis. This microscaled in vitro model, which validated previous in vivo preclinical work, revealed that mesoangioblasts showed unexpected efficiency as compared with myoblasts in dystrophin production. Consequently, this model may be used to predict efficacy of new drugs or therapies aimed at enhancing dystrophin accumulation and distribution before they are tested in vivo. SN - 2157-6564 UR - https://www.unboundmedicine.com/medline/citation/27502519/Skeletal_Muscle_Differentiation_on_a_Chip_Shows_Human_Donor_Mesoangioblasts'_Efficiency_in_Restoring_Dystrophin_in_a_Duchenne_Muscular_Dystrophy_Model_ L2 - https://doi.org/10.5966/sctm.2015-0053 DB - PRIME DP - Unbound Medicine ER -