Human circulating AC133⁺ stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle

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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