Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.
Development. 2012 Aug;139(16):2857-65. doi: 10.1242/dev.079665. Epub 2012 Jul 4.
Microenvironmental oxygen (O(2)) regulates stem cell activity, and a hypoxic niche with low oxygen levels has been reported in multiple stem cell types. Satellite cells are muscle-resident stem cells that maintain the homeostasis and mediate the regeneration of skeletal muscles. We demonstrate here that hypoxic culture conditions favor the quiescence of satellite cell-derived primary myoblasts by upregulating Pax7, a key regulator of satellite cell self-renewal, and downregulating MyoD and myogenin. During myoblast division, hypoxia promotes asymmetric self-renewal divisions and inhibits asymmetric differentiation divisions without affecting the overall rate of proliferation. Mechanistic studies reveal that hypoxia activates the Notch signaling pathway, which subsequently represses the expression of miR-1 and miR-206 through canonical Hes/Hey proteins, leading to increased levels of Pax7. More importantly, hypoxia conditioning enhances the efficiency of myoblast transplantation and the self-renewal of implanted cells. Given the robust effects of hypoxia on maintaining the quiescence and promoting the self-renewal of cultured myoblasts, we predict that oxygen levels in the satellite cell niche play a central role in precisely balancing quiescence versus activation, and self-renewal versus differentiation, in muscle stem cells in vivo.
微环境中的氧气（O(2)）调节干细胞活性，已有研究报道在多种干细胞类型中存在低氧水平的缺氧小生境。卫星细胞是肌肉驻留的干细胞，维持着骨骼肌的内稳态并介导其再生。我们在此证明，通过上调 Pax7（卫星细胞自我更新的关键调节因子）和下调 MyoD 和 myogenin，低氧培养条件有利于卫星细胞源性原代成肌细胞的静止。在成肌细胞分裂过程中，低氧促进不对称的自我更新分裂，抑制不对称的分化分裂，而不影响整体增殖速度。机制研究表明，低氧激活 Notch 信号通路，随后通过经典的 Hes/Hey 蛋白抑制 miR-1 和 miR-206 的表达，从而导致 Pax7 水平升高。更重要的是，低氧处理可提高成肌细胞移植的效率和植入细胞的自我更新能力。鉴于低氧对维持培养的成肌细胞静止和促进其自我更新具有强大的作用，我们预测卫星细胞小生境中的氧气水平在体内精确平衡肌肉干细胞的静止与激活、自我更新与分化方面发挥着核心作用。
