Engraftment of mesenchymal stem cells into dystrophin-deficient mice is not accompanied by functional recovery
Engraftment of mesenchymal stem cells into dystrophin-deficient mice is not accompanied by functional recovery
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DOI：
10.1016/j.yexcr.2009.05.009
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发表时间：
2009-09-10
影响因子：
3.7
通讯作者：
Perlingeiro, Rita C. R.
中科院分区：
文献类型：
--
作者：
Gang, Eun Ji;Darabi, Radbod;Perlingeiro, Rita C. R.
间充质干细胞制剂已被提出用于肌肉骨骼疾病的肌肉再生。尽管MSCs具有很大的体外扩增潜力，并具有分化为多种间充质细胞系的能力，但事实证明，诱导肌形成要困难得多。我们最近证实，Pax3是胚胎成肌程序的主要调节者，能够在体外将小鼠间充质干细胞系(MSCB9-Pax3)分化为成肌前体细胞。在这里，我们展示了将这些细胞注射到免疫缺陷小鼠心脏毒素损伤的肌肉中会导致肌肉肿瘤的发展，类似于横纹肌肉瘤。然后，我们将这些研究扩展到从骨髓中分离的原代人间充质干细胞(HMSCs)。在用编码PAX3的慢病毒载体进行基因修饰后，hMSCs激活了生肌程序，这一点从生肌调节因子的表达中可见一斑。在移植后，PAX3修饰的MSCs没有产生横纹肌肉瘤，而是产生了供体来源的肌纤维。在PAX3转导的hMSCs中，这些变化的频率比在模拟转导的MSCs中高。然而，无论是PAX3修饰的还是未修饰的MSCs的植入都没有导致收缩性能的改善。因此，这些发现表明，在骨髓间充质干细胞准备有效治疗肌营养不良之前，仍有局限性需要克服。(C)2009 Elsevier Inc.保留所有权利。
Mesenchymal stem cell preparations have been proposed for muscle regeneration in musculoskeletal disorders. Although MSCs have great in vitro expansion potential and possess the ability to differentiate into several mesenchymal lineages, myogenesis has proven to be much more difficult to induce. We have recently demonstrated that Pax3, the master regulator of the embryonic myogenic program, enables the in vitro differentiation of a murine mesenchymal stem cell line (MSCB9-Pax3) into myogenic progenitors. Here we show that injection of these cells into cardiotoxin-injured muscles of immunodeficient mice leads to the development of muscle tumors, resembling rhabdomyosarcomas. We then extended these studies to primary human mesenchymal stem cells (hMSCs) isolated from bone marrow. Upon genetic modification with a lentiviral vector encoding PAX3, hMSCs activated the myogenic program as demonstrated by expression of myogenic regulatory factors. Upon transplantation, the PAX3-modified MSCs did not generate rhabdomyosarcomas but rather, resulted in donor-derived myofibers. These were found at higher frequency in PAX3-transduced hMSCs than in mock-transduced MSCs. Nonetheless, neither engraftment of PAX3-modified or unmodified MSCs resulted in improved contractility. Thus these findings suggest that limitations remain to be overcome before MSC preparations result in effective treatment for muscular dystrophies. (C) 2009 Elsevier Inc. All rights reserved.