Gang Eun Ji, Darabi Radbod, Bosnakovski Darko, Xu Zhaohui, Kamm Kristine E, Kyba Michael, Perlingeiro Rita C R
Department of Developmental Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9133, USA.
Exp Cell Res. 2009 Sep 10;315(15):2624-36. doi: 10.1016/j.yexcr.2009.05.009. Epub 2009 May 19.
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.
间充质干细胞制剂已被提议用于肌肉骨骼疾病中的肌肉再生。尽管间充质干细胞具有巨大的体外扩增潜力，并具备分化为多种间充质谱系的能力，但已证明诱导其肌生成要困难得多。我们最近证明，胚胎肌生成程序的主要调节因子Pax3能够使小鼠间充质干细胞系（MSCB9 - Pax3）在体外分化为肌源性祖细胞。在此我们表明，将这些细胞注射到免疫缺陷小鼠的心脏毒素损伤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骨髓间充质干细胞（hMSCs）。在用编码PAX3的慢病毒载体进行基因改造后，hMSCs激活了肌生成程序，这通过肌源性调节因子的表达得以证明。移植后，PAX3修饰的间充质干细胞并未产生横纹肌肉瘤，而是产生了供体来源的肌纤维。在PAX3转导的hMSCs中发现这些肌纤维的频率高于模拟转导的间充质干细胞。尽管如此，PAX3修饰或未修饰的间充质干细胞的植入均未导致收缩力改善。因此，这些发现表明，在间充质干细胞制剂有效治疗肌肉营养不良症之前，仍有局限性有待克服。
