SP cells and downstream progenitors in human and mouse muscle

摘要 肌肉卫星细胞是骨骼肌中研究最多的细胞。它们满足了许多要求 组织特异性干细胞，包括自我更新和分化为多种细胞类型的能力。在……里面 除了卫星细胞外，还从人和小鼠的骨骼中分离出了其他肌祖细胞 肌肉。这些“另类”生肌祖细胞不同于卫星细胞，许多看起来是相关的 到微血管系统或在肌纤维之间的间隙。其中一种“另类”的肌源性细胞 种群是所谓的“边群”(SP)。我们对人类肌肉的研究表明，SP细胞 分泌因子(如BMP4)，诱导表达受体的肌源性祖细胞增殖 这些因子(BMP受体1a、BMPR1a)。在当前的应用程序中，我们将阐明 人肌肉SP细胞和BMPR1A+祖细胞研究BMPR1A在肌肉SP中的强制表达 细胞导致它们的激活和对肌源性谱系的承诺，研究BMPR1A+是否丢失 在表达Myf5或Pax3的骨骼肌祖细胞中表达将导致肌肉病理，以及 在小鼠模型中确定肌肉SP细胞或BMPR1A+祖细胞是否是具有 固有的高复制能力。这些研究的具体目标，包括人类和小鼠 目标1：确定人类肌肉SP细胞是否是BMPR1A+肌源性祖细胞的祖先；目标1 2：评估在人肌肉SP细胞中强制表达BMPR1A是否必要且足以诱导 目标3：研究BMPR1A+Myf5+或 BMPR1A+Pax3+前体细胞对肌肉发育和参与肌肉再生具有重要意义 出生后生活；目标4：使用m-TERT GFP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、BMPR1A+细胞或其他肌肉‘干细胞’的关系。这些研究将 揭示BMPR1A在肌祖细胞中表达的功能，并揭示人类与 肌肉SP和BMPR1A表达细胞。老鼠和人类的研究将相互协同，以 确定两个物种中每个肌原细胞群体的重要性和重要性。

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.