The effect of the muscle environment on the regenerative capacity of human skeletal muscle stem cells (Epidemiologic Perspectives & Innovations)

Background: Muscle stem cell transplantation is a possible treatment for muscular dystrophy. In addition to the intrinsic properties of the stem cells, the local and systemic environment plays an important role in determining the fate of the grafted cells. We therefore investigated the effect of modulating the host muscle environment in different ways (irradiation or cryoinjury or a combination of irradiation and cryoinjury) in two immunodeficient mouse strains (mdx nude and recombinase-activating gene (Rag)2-/γ chain-/C5-) on the regenerative capacity of two types of human skeletal muscle-derived stem cell (pericytes and CD133+ cells). Methods: Human skeletal muscle-derived pericytes or CD133+ cells were transplanted into muscles of either mdx nude or recombinase-activating gene (Rag)2-/γ chain-/C5-) host mice. Host muscles were modulated prior to donor cell transplantation by either irradiation, or cryoinjury, or a combination of irradiation and cryoinjury. Muscles were analysed four weeks after transplantation, by staining transverse cryostat sections of grafted muscles with antibodies to human lamin A/C, human spectrin, laminin and Pax 7. The number of nuclei and muscle fibres of donor origin and the number of satellite cells of both host and donor origin were quantified. Results: Within both host strains transplanted intra-muscularly with both donor cell types, there were significantly more nuclei and muscle fibres of donor origin in host muscles that had been modulated by cryoinjury, or irradiation+cryoinjury, than by irradiation alone. Irradiation has no additive effects in further enhancing the transplantation efficiency than cryodamage. Donor pericytes did not give rise to satellite cells. However, using CD133+ cells as donor cells, there were significantly more nuclei, muscle fibres, as well as satellite cells of donor origin in Rag2-/γ chain-/C5- mice than mdx nude mice, when the muscles were injured by either cryodamage or irradiation+cryodamage. Conclusions: Rag2-/γ chain-/C5- mice are a better recipient mouse strain than mdx nude mice for human muscle stem cell transplantation. Cryodamage of host muscle is the most effective method to enhance the transplantation efficiency of human skeletal muscle stem cells. This study highlights the importance of modulating the muscle environment in preclinical studies to optimise the efficacy of transplanted stem cells.