| Budget Amount *help |
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Muscular dystrophies are inherited disorders characterized by severe muscular degeneration and regeneration, resulting in severe muscular weakness and disability in daily living. From the cloning of dystrophin, the gene deficient in Duchenne muscular dystrophy (DMD), many responsible genes for muscular dystrophies have been isolated and complex pathogenesis leading to these disorders have been partially clarified. Clinically safe and effective treatment of these disorders, however, has not been developed yet. Mesenchymal stem cells derived from bone marrow have shown to be a distinct population of myogenic stem cells. Here we investigated whether the bone marrow transplantation (BMT), which has been widely applied as a safe therapeutic tool for hematological disorders, become a therapeutic potential for muscular dystrophy. Total bone marrow cells from green fluorescent protein (GFP) mice have been isolated as donor cells. We transplanted these cells into two types of muscular dystrophy
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models; dystrophin-deficient DMD model mice (mdx) and laminin-α2-deficient congenital muscular dystrophy type 1A (MDC1A) model mice (dy). BMT failed to produce significant improvement in muscle performance and muscular pathology, except for the restoration of dystrophin in some GFP positive myofibers in the mdx mice. In sharp contrast, BMT has led to a significant increase of life span in the dy mice. Physiological function of muscles including respiratory muscles in the dy mice has significantly improved by BMT. Immunohistochemical analysis of diaphragm from the dy mice after BMT, exhibited that over 60% myofibers were GFP-positive and over 80% myofibers expressed laminin-α2. These findings gave rise to a possibility that some muscular dystrophies with basement membrane disruption, such as MDC 1A were more responsive to BMT than those with plasma membrane disruption, such as DMD. Thus we further investigated the efficacy of BMT on another mouse model of muscular dystrophy, Fukuyama type congenital muscular dystrophy (FCMD), which showed severe basement membrane disruption. Compared to the mdx mice, the FCMD model mice showed increased GFP-positive myofibers in diaphragm after BMT. Additionally, we found that a treatment of basement membrane disruption in muscles of wild-type mice significantly increased many GFP-positive myofibers after BMT. Our results may open the avenue for clinically safe and effective treatment for muscular dystrophy by BMT. Less
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