Transplantation of genetically corrected human iPSC-derived progenitors in mice with limb-girdle muscular dystrophy

Francesco Saverio Tedesco, Mattia F M Gerli, Laura Perani, Sara Benedetti, Federica Ungaro, Marco Cassano, Stefania Antonini, Enrico Tagliafico, Valentina Artusi, Emanuela Longa, Rossana Tonlorenzi, Martina Ragazzi, Giorgia Calderazzi, Hidetoshi Hoshiya, Ornella Cappellari, Marina Mora, Benedikt Schoser, Peter Schneiderat, Mitsuo Oshimura, Roberto BottinelliMaurilio Sampaolesi, Yvan Torrente, Vania Broccoli, Giulio Cossu

Research output: Contribution to journalArticle

154 Citations (Scopus)

Abstract

Mesoangioblasts are stem/progenitor cells derived from a subset of pericytes found in muscle that express alkaline phosphatase. They have been shown to ameliorate the disease phenotypes of different animal models of muscular dystrophy and are now undergoing clinical testing in children affected by Duchenne's muscular dystrophy. Here, we show that patients with a related disease, limb-girdle muscular dystrophy 2D (LGMD2D), which is caused by mutations in the gene encoding α-sarcoglycan, have reduced numbers of this pericyte subset and thus produce too few mesoangioblasts for use in autologous cell therapy. Hence, we reprogrammed fibroblasts and myoblasts from LGMD2D patients to generate human induced pluripotent stem cells (iPSCs) and developed a protocol for the derivation of mesoangioblast-like cells from these iPSCs. The iPSC-derived mesoangioblasts were expanded and genetically corrected in vitro with a lentiviral vector carrying the gene encoding human α-sarcoglycan and a promoter that would ensure expression only in striated muscle. When these genetically corrected human iPSC-derived mesoangioblasts were transplanted into α-sarcoglycan-null immunodeficient mice, they generated muscle fibers that expressed α-sarcoglycan. Finally, transplantation of mouse iPSC-derived mesoangioblasts into α-sarcoglycan-null immunodeficient mice resulted in functional amelioration of the dystrophic phenotype and restoration of the depleted progenitors. These findings suggest that transplantation of genetically corrected mesoangioblast-like cells generated from iPSCs from LGMD2D patients may be useful for treating this type of muscular dystrophy and perhaps other forms of muscular dystrophy as well.

Original languageEnglish
Article number140ra89
JournalScience Translational Medicine
Volume4
Issue number140
DOIs
Publication statusPublished - Jun 27 2012

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Limb-Girdle Muscular Dystrophies
Induced Pluripotent Stem Cells
Sarcoglycans
Transplantation
Pericytes
Muscular Dystrophies
Animal Muscular Dystrophy
Stem Cells
Phenotype
Muscles
Striated Muscle
Duchenne Muscular Dystrophy
Myoblasts
Cell- and Tissue-Based Therapy
Genes
Alkaline Phosphatase
Animal Models
Fibroblasts
Mutation

ASJC Scopus subject areas

  • Medicine(all)

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Transplantation of genetically corrected human iPSC-derived progenitors in mice with limb-girdle muscular dystrophy. / Tedesco, Francesco Saverio; Gerli, Mattia F M; Perani, Laura; Benedetti, Sara; Ungaro, Federica; Cassano, Marco; Antonini, Stefania; Tagliafico, Enrico; Artusi, Valentina; Longa, Emanuela; Tonlorenzi, Rossana; Ragazzi, Martina; Calderazzi, Giorgia; Hoshiya, Hidetoshi; Cappellari, Ornella; Mora, Marina; Schoser, Benedikt; Schneiderat, Peter; Oshimura, Mitsuo; Bottinelli, Roberto; Sampaolesi, Maurilio; Torrente, Yvan; Broccoli, Vania; Cossu, Giulio.

In: Science Translational Medicine, Vol. 4, No. 140, 140ra89, 27.06.2012.

Research output: Contribution to journalArticle

Tedesco, FS, Gerli, MFM, Perani, L, Benedetti, S, Ungaro, F, Cassano, M, Antonini, S, Tagliafico, E, Artusi, V, Longa, E, Tonlorenzi, R, Ragazzi, M, Calderazzi, G, Hoshiya, H, Cappellari, O, Mora, M, Schoser, B, Schneiderat, P, Oshimura, M, Bottinelli, R, Sampaolesi, M, Torrente, Y, Broccoli, V & Cossu, G 2012, 'Transplantation of genetically corrected human iPSC-derived progenitors in mice with limb-girdle muscular dystrophy', Science Translational Medicine, vol. 4, no. 140, 140ra89. https://doi.org/10.1126/scitranslmed.3003541
Tedesco, Francesco Saverio ; Gerli, Mattia F M ; Perani, Laura ; Benedetti, Sara ; Ungaro, Federica ; Cassano, Marco ; Antonini, Stefania ; Tagliafico, Enrico ; Artusi, Valentina ; Longa, Emanuela ; Tonlorenzi, Rossana ; Ragazzi, Martina ; Calderazzi, Giorgia ; Hoshiya, Hidetoshi ; Cappellari, Ornella ; Mora, Marina ; Schoser, Benedikt ; Schneiderat, Peter ; Oshimura, Mitsuo ; Bottinelli, Roberto ; Sampaolesi, Maurilio ; Torrente, Yvan ; Broccoli, Vania ; Cossu, Giulio. / Transplantation of genetically corrected human iPSC-derived progenitors in mice with limb-girdle muscular dystrophy. In: Science Translational Medicine. 2012 ; Vol. 4, No. 140.
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AU - Benedetti, Sara

AU - Ungaro, Federica

AU - Cassano, Marco

AU - Antonini, Stefania

AU - Tagliafico, Enrico

AU - Artusi, Valentina

AU - Longa, Emanuela

AU - Tonlorenzi, Rossana

AU - Ragazzi, Martina

AU - Calderazzi, Giorgia

AU - Hoshiya, Hidetoshi

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AU - Mora, Marina

AU - Schoser, Benedikt

AU - Schneiderat, Peter

AU - Oshimura, Mitsuo

AU - Bottinelli, Roberto

AU - Sampaolesi, Maurilio

AU - Torrente, Yvan

AU - Broccoli, Vania

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