Bachrach Estanislao, Perez Antonio L, Choi Yeong-Hoon, Illigens Ben M W, Jun Susan J, del Nido Pedro, McGowan Francis X, Li Sheng, Flint Alan, Chamberlain Jeffrey, Kunkel Louis M
Howard Hughes Medical Institute, Program in Genomics, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
Muscle Nerve. 2006 Jul;34(1):44-52. doi: 10.1002/mus.20560.
Cell-based therapy continues to be a promising avenue for the treatment of Duchenne muscular dystrophy (DMD), an X-linked skeletal muscle-wasting disease. Recently, we demonstrated that freshly isolated myogenic progenitors contained within the adult skeletal muscle side population (SP) can engraft into dystrophic fibers of nonirradiated mdx(5cv) mice after intravenous transplantation. Engraftment rates, however, have not been therapeutically significant, achieving at most 1% of skeletal muscle myofibers expressing protein from donor-derived nuclei. To enhance the engraftment of transplanted myogenic progenitors, an intraarterial delivery method was adapted from a previously described procedure. Cultured, lentivirus-transduced skeletal muscle SP cells, derived from mdx(5cv) mice, were transplanted into the femoral artery of noninjured mdx(5cv) mice. Based on the expression of microdystrophin or green fluorescent protein (GFP) transgenes in host muscle, sections of the recipient muscles exhibited 5%-8% of skeletal muscle fibers expressing donor-derived transgenes. Further, donor muscle SP cells, which did not express any myogenic markers prior to transplant, expressed the satellite cell transcription factor, Pax7, and the muscle-specific intermediate filament, desmin, after extravasation into host muscle. The expression of these muscle-specific markers indicates that progenitors within the side population can differentiate along the myogenic lineage after intraarterial transplantation and extravasation into host muscle. Given that femoral artery catheterization is a common, safe clinical procedure and that the transplantation of cultured adult muscle progenitor cells has proven to be safe in mice, our data may represent a step toward the improvement of cell-based therapies for DMD and other myogenic disorders.
基于细胞的疗法仍然是治疗杜氏肌营养不良症（DMD）的一个有前景的途径，DMD是一种X连锁的骨骼肌萎缩疾病。最近，我们证明了成年骨骼肌侧群（SP）中新鲜分离的肌源性祖细胞在静脉移植后可以植入未受辐射的mdx(5cv)小鼠的营养不良纤维中。然而，植入率在治疗上并不显著，最多只有1%的骨骼肌肌纤维表达来自供体细胞核的蛋白质。为了提高移植的肌源性祖细胞的植入率，我们采用了一种先前描述的程序中的动脉内递送方法。将源自mdx(5cv)小鼠的培养的、慢病毒转导的骨骼肌SP细胞移植到未受伤的mdx(5cv)小鼠的股动脉中。根据宿主肌肉中微肌营养不良蛋白或绿色荧光蛋白（GFP）转基因的表达情况，受体肌肉切片显示有5%-8%的骨骼肌纤维表达供体来源的转基因。此外，供体肌肉SP细胞在移植前不表达任何肌源性标记物，在渗入宿主肌肉后表达卫星细胞转录因子Pax7和肌肉特异性中间丝结蛋白。这些肌肉特异性标记物的表达表明，侧群中的祖细胞在动脉内移植并渗入宿主肌肉后可以沿着肌源性谱系分化。鉴于股动脉插管是一种常见、安全的临床操作，并且培养的成年肌肉祖细胞的移植在小鼠中已被证明是安全的，我们的数据可能代表着朝着改善DMD和其他肌源性疾病的基于细胞的疗法迈出了一步。
