Muscle CD31(-) CD45(-) side population cells promote muscle regeneration by stimulating proliferation and migration of myoblasts
Muscle CD31(-) CD45(-) side population cells promote muscle regeneration by stimulating proliferation and migration of myoblasts
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DOI：
10.2353/ajpath.2008.070902
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发表时间：
2008-09-01
影响因子：
6
通讯作者：
Takeda, Shin'ichi
中科院分区：
文献类型：
--
作者：
Motohashi, Norio;Uezumi, Akiyoshi;Takeda, Shin'ichi
CD31(-) CD45（-）侧群（SP）细胞是一个较小的SP亚群，在未损伤的骨骼肌中具有间充质干细胞样特性，但可以在肌肉损伤时扩展。为了明确这些SP细胞在肌肉再生中的作用，我们将绿色荧光蛋白（GFP）阳性的成肌细胞(含或不含CD31（-) CD45(-) SP细胞）注射到免疫缺陷NOD/scid小鼠或肌营养不良蛋白缺陷mdx小鼠的胫骨前肌中。在mdx和NOD/scid肌肉中，共移植后形成的GFP阳性纤维比GFP阳性成肌细胞移植后形成的多。此外，移植后的成肌细胞比单独移植后的成肌细胞分布更广泛。抗磷酸化组蛋白H3抗体免疫组化显示CD31(-) CD45(-) SP细胞刺激了共移植成肌细胞的细胞分裂。全基因组基因表达分析表明，这些SP细胞特异性表达多种细胞外基质蛋白、膜蛋白和细胞因子。我们还发现它们表达高水平的基质金属蛋白酶-2 mRNA和明胶酶活性。此外，来自CD31(-) CD45(-) SP细胞的基质金属蛋白酶-2促进了体内成肌细胞的迁移。我们的研究结果表明，CD31(-) CD45(-) SP细胞通过促进成肌细胞的增殖和迁移来支持肌肉再生。进一步研究肌肉再生的分子和细胞机制将有助于肌肉萎缩症细胞疗法的发展。
CD31(-) CD45(-) side population (SP) cells are a minor SP subfraction that have mesenchymal stem cell-like properties in uninjured skeletal muscle but that can expand on muscle injury. To clarify the role of these SP cells in muscle regeneration, we injected green fluorescent protein (GFP)positive myoblasts with or without CD31(-) CD45(-) SP cells into die tibialis anterior muscles of immunodeficient NOD/scid mice or dystrophin-deficient mdx mice. More GFP positive fibers were formed after co-transplantation than after transplantation of GFP positive myoblasts atone in both mdx and NOD/scid muscles. Moreover, grafted myoblasts were more widely distributed after co-transplantation than after transplantation of myoblasts atone. Immunohistochemistry with anti-phosphorylated histone H3 antibody revealed that CD31(-) CD45(-) SP cells stimulated cell division of co-grafted myoblasts. Genome-wide gene expression analyses showed that these SP cells specifically express a variety of extracellular matrix proteins, membrane proteins, and cytokines. We also found that they express high levels of matrix metalloproteinase-2 mRNA and gelatinase activity Furthermore, matrix metal loproteinase-2 derived from CD31(-) CD45(-) SP cells promoted migration of myoblasts in vivo. Our results suggest that CD31(-) CD45(-) SP cells support muscle regeneration by promoting proliferation and migration of myoblasts. Future studies to further define the molecular and cellular mechanisms of muscle regeneration will aid in the development of cell therapies for muscular dystrophy.