National Research Council, Institute of Cell Biology and Neurobiology, Fondazione Santa Lucia, Roma, Italy.
Stem Cells. 2013 Nov;31(11):2478-91. doi: 10.1002/stem.1487.
Satellite cells are mitotically quiescent myogenic stem cells resident beneath the basal lamina surrounding adult muscle myofibers. In response to injury, multiple extrinsic signals drive the entry of satellite cells into the cell cycle and then to proliferation, differentiation, and self-renewal of their downstream progeny. Because satellite cells must endure for a lifetime, their cell cycle activity must be carefully controlled to coordinate proliferative expansion and self-renewal with the onset of the differentiation program. In this study, we find that cyclin D3, a member of the family of mitogen-activated D-type cyclins, is critically required for proper developmental progression of myogenic progenitors. Using a cyclin D3-knockout mouse we determined that cyclin D3 deficiency leads to reduced myofiber size and impaired establishment of the satellite cell population within the adult muscle. Cyclin D3-null myogenic progenitors, studied ex vivo on isolated myofibers and in vitro, displayed impaired cell cycle progression, increased differentiation potential, and reduced self-renewal capability. Similarly, silencing of cyclin D3 in C2 myoblasts caused anticipated exit from the cell cycle and precocious onset of terminal differentiation. After induced muscle damage, cyclin D3-null myogenic progenitors exhibited proliferation deficits, a precocious ability to form newly generated myofibers and a reduced capability to repopulate the satellite cell niche at later stages of the regeneration process. These results indicate that cyclin D3 plays a cell-autonomous and nonredundant function in regulating the dynamic balance between proliferation, differentiation, and self-renewal that normally establishes an appropriate pool size of adult satellite cells.
卫星细胞是位于成年肌纤维基底膜下的有丝分裂静止的成肌干细胞。在受到损伤时，多种外在信号驱动卫星细胞进入细胞周期，然后进行增殖、分化，并自我更新其下游祖细胞。由于卫星细胞必须终生存在，其细胞周期活动必须受到严格控制，以协调增殖扩张和自我更新与分化程序的启动。在这项研究中，我们发现细胞周期蛋白 D3（一种有丝分裂激活的 D 型细胞周期蛋白家族成员）对于成肌祖细胞的正常发育进展至关重要。使用细胞周期蛋白 D3 敲除小鼠，我们确定细胞周期蛋白 D3 缺乏会导致肌纤维大小减小，并损害成年肌肉中卫星细胞群体的建立。在体外的分离肌纤维和体外培养中研究细胞周期蛋白 D3 缺陷的成肌祖细胞时，发现其细胞周期进程受损，分化潜能增加，自我更新能力降低。同样，在 C2 成肌细胞中沉默细胞周期蛋白 D3 会导致预期的细胞周期退出和终末分化的提前发生。在诱导的肌肉损伤后，细胞周期蛋白 D3 缺陷的成肌祖细胞表现出增殖缺陷，过早地形成新生成的肌纤维的能力，以及在再生过程的后期重新填充卫星细胞龛的能力降低。这些结果表明，细胞周期蛋白 D3 在调节增殖、分化和自我更新之间的动态平衡中发挥自主且非冗余的功能，这种平衡通常会建立适当的成年卫星细胞池大小。
