Human circulating AC133+ stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle
Yvan Torrente, Marzia Belicchi, Maurilio Sampaolesi, Federica Pisati, Mirella Meregalli, Giuseppe D’Antona, Rossana Tonlorenzi, Laura Porretti, Manuela Gavina, Kamel Mamchaoui, Maria Antonietta Pellegrino, Denis Furling, Vincent Mouly, Gillian S. Butler-Browne, Roberto Bottinelli, Giulio Cossu, Nereo Bresolin
Yvan Torrente, Marzia Belicchi, Maurilio Sampaolesi, Federica Pisati, Mirella Meregalli, Giuseppe D’Antona, Rossana Tonlorenzi, Laura Porretti, Manuela Gavina, Kamel Mamchaoui, Maria Antonietta Pellegrino, Denis Furling, Vincent Mouly, Gillian S. Butler-Browne, Roberto Bottinelli, Giulio Cossu, Nereo Bresolin
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Human circulating AC133+ stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle

Abstract

Duchenne muscular dystrophy (DMD) is a common X-linked disease characterized by widespread muscle damage that invariably leads to paralysis and death. There is currently no therapy for this disease. Here we report that a subpopulation of circulating cells expressing AC133, a well-characterized marker of hematopoietic stem cells, also expresses early myogenic markers. Freshly isolated, circulating AC133+ cells were induced to undergo myogenesis when cocultured with myogenic cells or exposed to Wnt-producing cells in vitro and when delivered in vivo through the arterial circulation or directly into the muscles of transgenic scid/mdx mice (which allow survival of human cells). Injected cells also localized under the basal lamina of host muscle fibers and expressed satellite cell markers such as M-cadherin and MYF5. Furthermore, functional tests of injected muscles revealed a substantial recovery of force after treatment. As these cells can be isolated from the blood, manipulated in vitro, and delivered through the circulation, they represent a possible tool for future cell therapy applications in DMD disease or other muscular dystrophies.

Authors

Yvan Torrente, Marzia Belicchi, Maurilio Sampaolesi, Federica Pisati, Mirella Meregalli, Giuseppe D’Antona, Rossana Tonlorenzi, Laura Porretti, Manuela Gavina, Kamel Mamchaoui, Maria Antonietta Pellegrino, Denis Furling, Vincent Mouly, Gillian S. Butler-Browne, Roberto Bottinelli, Giulio Cossu, Nereo Bresolin

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Characterization and clonal isolation of muscle-derived cells that emerg...
Characterization and clonal isolation of muscle-derived cells that emerged from the explants of TA muscles injected with human circulating AC133+ cells. (A–C) Cells from transplanted muscle explants were cultivated in vitro and analyzed after 7 days (A, phase contrast) for coexpression of M-cadherin (B) and human lamin A/C (C). (D) Double immunocytochemistry with antibodies against desmin (green) and human lamin A/C (red) demonstrated the presence of human myogenic cells (arrowheads) after 6 weeks of explant culture. For cloning, single cells within the explant-derived cells were plated in proliferative conditions as described in Methods. (E) Human myogenic clones obtained from clone A1 express several specific myogenic human markers, as assessed by RT-PCR. The C2C12 murine cell line (lane –) and a human cDNA library (lane +) were used as controls. (F and G) A1-derived cells differentiated well into myotubes coexpressing the late myogenic marker MyHC (red in F) and human MYOD (green in G).