Darabi Radbod, Baik June, Clee Mark, Kyba Michael, Tupler Rossella, Perlingeiro Rita C R
Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Exp Neurol. 2009 Nov;220(1):212-6. doi: 10.1016/j.expneurol.2009.08.002. Epub 2009 Aug 13.
Muscular dystrophies (MDs) consist of a genetically heterogeneous group of disorders, recessive or dominant, characterized by progressive skeletal muscle weakening. To date, no effective treatment is available. Experimental strategies pursuing muscle regeneration through the transplantation of stem cell preparations have brought hope to patients affected by this disorder. Efficacy has been demonstrated in recessive MD models through contribution of wild-type nuclei to the muscle fiber heterokaryon; however, to date, there has been no study investigating the efficacy of a cell therapy in a dominant model of MD. We have recently demonstrated that Pax3-induced embryonic stem (ES) cell-derived myogenic progenitors are able to engraft and improve muscle function in mdx mice, a recessive mouse model for Duchenne MD. To assess whether this therapeutic effect can be extended to a dominant type of muscle disorder, here we transplanted these cells into FRG1 transgenic mice, a dominant model that has been associated with facioscapulohumeral muscular dystrophy. Our results show that Pax3-induced ES-derived myogenic progenitors are capable of significant engraftment after intramuscular or systemic transplantation into Frg1 mice. Analyses of contractile parameters revealed functional improvement in treated muscles of male mice, but not females, which are less severely affected. This study is the first to use Frg1 transgenic mice to assess muscle regeneration as well as to support the use of a cell-based therapy for autosomal dominant types of MD.
肌营养不良症（MDs）是一组由遗传异质性疾病组成的疾病，有隐性或显性之分，其特征是进行性骨骼肌衰弱。迄今为止，尚无有效的治疗方法。通过移植干细胞制剂来促进肌肉再生的实验策略给受这种疾病影响的患者带来了希望。在隐性MD模型中，通过野生型细胞核对肌纤维异核体的贡献已证明了其疗效；然而，迄今为止，尚无研究调查细胞疗法在MD显性模型中的疗效。我们最近证明，Pax3诱导的胚胎干细胞（ES）来源的成肌祖细胞能够植入mdx小鼠（杜氏肌营养不良症的隐性小鼠模型）并改善其肌肉功能。为了评估这种治疗效果是否可以扩展到显性类型的肌肉疾病，我们在此将这些细胞移植到FRG1转基因小鼠中，这是一种与面肩肱型肌营养不良症相关的显性模型。我们的结果表明，Pax3诱导的ES来源的成肌祖细胞在肌肉内或全身移植到Frg1小鼠后能够显著植入。对收缩参数的分析显示，雄性小鼠经治疗的肌肉功能有所改善，但雌性小鼠（受影响较轻）则没有。这项研究首次使用Frg1转基因小鼠来评估肌肉再生，并支持将基于细胞的疗法用于常染色体显性类型的MD。
