Stuelsatz Pascal, Shearer Andrew, Li Yunfei, Muir Lindsey A, Ieronimakis Nicholas, Shen Qingwu W, Kirillova Irina, Yablonka-Reuveni Zipora
Department of Biological Structure, University of Washington School of Medicine, Seattle, WA, USA.
Program in Molecular and Cellular Biology and Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA.
Dev Biol. 2015 Jan 1;397(1):31-44. doi: 10.1016/j.ydbio.2014.08.035. Epub 2014 Sep 16.
Extraocular muscles (EOMs) are highly specialized skeletal muscles that originate from the head mesoderm and control eye movements. EOMs are uniquely spared in Duchenne muscular dystrophy and animal models of dystrophin deficiency. Specific traits of myogenic progenitors may be determinants of this preferential sparing, but very little is known about the myogenic cells in this muscle group. While satellite cells (SCs) have long been recognized as the main source of myogenic cells in adult muscle, most of the knowledge about these cells comes from the prototypic limb muscles. In this study, we show that EOMs, regardless of their distinctive Pax3-negative lineage origin, harbor SCs that share a common signature (Pax7(+), Ki67(-), Nestin-GFP(+), Myf5(nLacZ+), MyoD-positive lineage origin) with their limb and diaphragm somite-derived counterparts, but are remarkably endowed with a high proliferative potential as revealed in cell culture assays. Specifically, we demonstrate that in adult as well as in aging mice, EOM SCs possess a superior expansion capacity, contributing significantly more proliferating, differentiating and renewal progeny than their limb and diaphragm counterparts. These robust growth and renewal properties are maintained by EOM SCs isolated from dystrophin-null (mdx) mice, while SCs from muscles affected by dystrophin deficiency (i.e., limb and diaphragm) expand poorly in vitro. EOM SCs also retain higher performance in cell transplantation assays in which donor cells were engrafted into host mdx limb muscle. Collectively, our study provides a comprehensive picture of EOM myogenic progenitors, showing that while these cells share common hallmarks with the prototypic SCs in somite-derived muscles, they distinctively feature robust growth and renewal capacities that warrant the title of high performance myo-engines and promote consideration of their properties for developing new approaches in cell-based therapy to combat skeletal muscle wasting.
眼外肌（EOMs）是高度特化的骨骼肌，起源于头部中胚层，控制眼球运动。在杜兴氏肌营养不良症和肌营养不良蛋白缺乏的动物模型中，眼外肌具有独特的幸免情况。肌源性祖细胞的特定特征可能是这种优先幸免的决定因素，但对于该肌肉群中的肌源性细胞知之甚少。虽然卫星细胞（SCs）长期以来一直被认为是成年肌肉中肌源性细胞的主要来源，但关于这些细胞的大部分知识都来自典型的肢体肌肉。在本研究中，我们表明，无论其独特的Pax3阴性谱系起源如何，眼外肌都含有与肢体和膈肌体节衍生的卫星细胞具有共同特征（Pax7(+)、Ki67(-)、Nestin-GFP(+)、Myf5(nLacZ+)、MyoD阳性谱系起源）的卫星细胞，但在细胞培养试验中显示出具有显著的高增殖潜力。具体而言，我们证明，在成年和衰老小鼠中，眼外肌卫星细胞具有卓越的扩增能力，其增殖、分化和更新后代的数量明显多于肢体和膈肌的卫星细胞。从肌营养不良蛋白缺失（mdx）小鼠分离的眼外肌卫星细胞保持了这些强大的生长和更新特性，而受肌营养不良蛋白缺乏影响的肌肉（即肢体和膈肌）中的卫星细胞在体外扩增能力较差。在将供体细胞移植到宿主mdx肢体肌肉的细胞移植试验中，眼外肌卫星细胞也表现出更高的性能。总的来说，我们的研究提供了眼外肌肌源性祖细胞的全面情况，表明虽然这些细胞与体节衍生肌肉中的典型卫星细胞具有共同特征，但它们具有独特的强大生长和更新能力，无愧于高性能肌引擎的称号，并促使人们考虑其特性，以开发基于细胞的治疗方法来对抗骨骼肌萎缩。
