SP cells and downstream progenitors in human and mouse muscle

摘要 肌卫星细胞是骨骼肌中研究最多的细胞。他们满足了许多要求， 组织特异性干细胞，包括自我更新和分化成多种细胞类型的能力。在 除了卫星细胞外，还从人和小鼠骨骼肌中分离出了其他肌源性祖细胞， 肌肉.这些“替代性”肌源性祖细胞与卫星细胞不同， 微血管或肌纤维间的间隙中。其中一种“替代性”肌原细胞 这就是所谓的“侧群”（SP）。我们对人体肌肉的研究表明，SP细胞 分泌因子（如BMP 4），诱导表达受体的肌原性祖细胞增殖， 这些因子（BMP-受体1a，BMPR 1a）。在本申请中，我们将阐明 人肌肉SP细胞和BMPR 1a+祖细胞，研究BMPR 1a是否在肌肉SP中强制表达 细胞导致其激活和定向成肌细胞谱系，研究BMPR 1a + 在表达Myf 5或Pax 3的骨骼肌祖细胞中的表达将导致肌肉病理学，并且 在小鼠模型中确定肌肉SP细胞或BMPR 1a+祖细胞是否是“干”样细胞， 内在的高复制能力。这些研究的具体目的，涉及人类和小鼠 目的1：确定人肌肉SP细胞是否是BMPR 1a+肌源性祖细胞的“祖先”;目的 2：评估BMPR 1a在人肌肉SP细胞中的强制表达是否是必要的且足以诱导 目的3：研究BMPR 1a + Myf 5+或 BMPR 1a + Pax 3+祖细胞对肌肉发育很重要，并参与肌肉再生。 目的4：使用m-TERTGFP模型鉴定骨骼肌中表达端粒酶的细胞 并确定它们与肌肉SP、BMPR 1a+细胞或其他肌肉“干”细胞的关系。这些研究将 揭示BMPR 1a在肌肉祖细胞中表达的功能，并阐明人与骨骼肌细胞间的关系。 肌肉SP和BMPR 1a表达细胞。小鼠和人类研究将相互协同， 定义两个物种中每个肌源性细胞群的意义和重要性。

ABSTRACT Muscle satellite cells are the most studied cells in skeletal muscle. They fulfill many of the requirements of tissue-specific stem cells, including the ability to self-renew and to differentiate into multiple cell types. In addition to satellite cells, other myogenic progenitors have been isolated from both human and mouse skeletal muscle. These 'alternative' myogenic progenitors are distinct from satellite cells and many appear associated to the microvasculature or in the interstitial spaces between myofibers. One of these 'alternative' myogenic cell populations is the so-called 'side population' (SP). Our studies in human muscle have proposed that SP cells secrete factors (such as BMP4) that induce the proliferation of myogenic progenitors expressing receptors for these factors (BMP-receptor 1a, BMPR1a). In the current application, we will elucidate the ties between human muscle SP cells and BMPR1a+ progenitors, study whether forced expression of BMPR1a in muscle SP cells leads to their activation and commitment to the myogenic lineage, investigate if loss of BMPR1a+ expression in skeletal muscle progenitors expressing Myf5 or Pax3 will lead to muscle pathology, and determine in a mouse model whether muscle SP cells or BMPR1a+ progenitors are 'stem'-like cells with intrinsic high-replicative capacity. The Specific Aims of these studies, which involve both human and mouse cells, are: Aim 1: Determine if human muscle SP cells are 'ancestors' of BMPR1a+ myogenic progenitors; Aim 2: Assess if forced expression of BMPR1a in human muscle SP cells is necessary and sufficient to induce their proliferation and specification towards the myogenic lineage; Aim 3: Investigate if BMPR1a+Myf5+ or BMPR1a+Pax3+ progenitors are important for muscle development and participate in muscle regeneration in post-natal life; Aim 4: Use the m-TERT GFP model to identify telomerase-expressing cells in skeletal muscle and determine their relationship to muscle SP, BMPR1a+ cells or other muscle 'stem' cells. These studies will unveil the function of BMPR1a expression in muscle progenitors and unravel the relationship between human muscle SP and BMPR1a-expressing cells. Mouse and human studies will synergize with one another, to define the significance and importance of each myogenic cell population in both species.