Chan Jerry, O'Donoghue Keelin, Gavina Manuela, Torrente Yvan, Kennea Nigel, Mehmet Huseyin, Stewart Helen, Watt Diana J, Morgan Jennifer E, Fisk Nicholas M
Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom.
Stem Cells. 2006 Aug;24(8):1879-91. doi: 10.1634/stemcells.2005-0564. Epub 2006 May 4.
Cell therapy for degenerative muscle diseases such as the muscular dystrophies requires a source of cells with the capacity to participate in the formation of new muscle fibers. We investigated the myogenic potential of human fetal mesenchymal stem cells (hfMSCs) using a variety of stimuli. The use of 5-azacytidine or steroids did not produce skeletal muscle differentiation, whereas myoblast-conditioned medium resulted in only 1%-2% of hfMSCs undergoing muscle differentiation. However, in the presence of galectin-1, 66.1% +/- 5.7% of hfMSCs, but not adult bone marrow-derived mesenchymal stem cells, assumed a muscle phenotype, forming long, multinucleated fibers expressing both desmin and sarcomeric myosin via activation of muscle regulatory factors. Continuous exposure to galectin-1 resulted in more efficient muscle differentiation than pulsed exposure (62.3% vs. 39.1%; p < .001). When transplanted into regenerating murine muscle, galectin-1-exposed hfMSCs formed fourfold more human muscle fibers than nonstimulated hfMSCs (p = .008), with similar results obtained in a scid/mdx dystrophic mouse model. These data suggest that hfMSCs readily undergo muscle differentiation in response to galectin-1 through a stepwise progression similar to that which occurs during embryonic myogenesis. The high degree of myogenic conversion achieved by this method has relevance for the development of therapies for muscular dystrophies.
针对诸如肌营养不良症等退行性肌肉疾病的细胞疗法需要有能够参与新肌纤维形成的细胞来源。我们使用多种刺激因素研究了人胎儿间充质干细胞（hfMSCs）的成肌潜力。使用5-氮杂胞苷或类固醇并未导致骨骼肌分化，而成肌细胞条件培养基仅使1%-2%的hfMSCs发生肌肉分化。然而，在半乳糖凝集素-1存在的情况下，66.1%±5.7%的hfMSCs（而非成人骨髓来源的间充质干细胞）呈现出肌肉表型，通过激活肌肉调节因子形成表达结蛋白和肌节肌球蛋白的长的多核纤维。持续暴露于半乳糖凝集素-1比脉冲暴露导致更有效的肌肉分化（62.3%对39.1%；p<.001）。当移植到再生的小鼠肌肉中时，经半乳糖凝集素-1处理的hfMSCs形成的人肌纤维比未刺激的hfMSCs多四倍（p = .008），在scid/mdx营养不良小鼠模型中也获得了类似结果。这些数据表明，hfMSCs通过类似于胚胎肌生成过程中发生的逐步进展，对半乳糖凝集素-1作出反应，容易发生肌肉分化。通过这种方法实现的高度成肌转化与肌营养不良症治疗方法的开发相关。
