Ratnayake Dhanushika, Nguyen Phong D, Rossello Fernando J, Wimmer Verena C, Tan Jean L, Galvis Laura A, Julier Ziad, Wood Alasdair J, Boudier Thomas, Isiaku Abdulsalam I, Berger Silke, Oorschot Viola, Sonntag Carmen, Rogers Kelly L, Marcelle Christophe, Lieschke Graham J, Martino Mikaël M, Bakkers Jeroen, Currie Peter D
Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
EMBL Australia, Monash University, Clayton, Victoria, Australia.
Nature. 2021 Mar;591(7849):281-287. doi: 10.1038/s41586-021-03199-7. Epub 2021 Feb 10.
Skeletal muscle regenerates through the activation of resident stem cells. Termed satellite cells, these normally quiescent cells are induced to proliferate by wound-derived signals. Identifying the source and nature of these cues has been hampered by an inability to visualize the complex cell interactions that occur within the wound. Here we use muscle injury models in zebrafish to systematically capture the interactions between satellite cells and the innate immune system after injury, in real time, throughout the repair process. This analysis revealed that a specific subset of macrophages 'dwell' within the injury, establishing a transient but obligate niche for stem cell proliferation. Single-cell profiling identified proliferative signals that are secreted by dwelling macrophages, which include the cytokine nicotinamide phosphoribosyltransferase (Nampt, which is also known as visfatin or PBEF in humans). Nampt secretion from the macrophage niche is required for muscle regeneration, acting through the C-C motif chemokine receptor type 5 (Ccr5), which is expressed on muscle stem cells. This analysis shows that in addition to their ability to modulate the immune response, specific macrophage populations also provide a transient stem-cell-activating niche, directly supplying proliferation-inducing cues that govern the repair process that is mediated by muscle stem cells. This study demonstrates that macrophage-derived niche signals for muscle stem cells, such as NAMPT, can be applied as new therapeutic modalities for skeletal muscle injury and disease.
骨骼肌通过激活驻留干细胞实现再生。这些干细胞被称为卫星细胞，通常处于静止状态，受伤口来源的信号诱导而增殖。由于无法可视化伤口内发生的复杂细胞相互作用，确定这些信号的来源和性质受到了阻碍。在这里，我们利用斑马鱼的肌肉损伤模型，在整个修复过程中实时系统地捕捉损伤后卫星细胞与先天免疫系统之间的相互作用。该分析表明，特定亚群的巨噬细胞“驻留”在损伤部位，为干细胞增殖建立了一个短暂但必不可少的微环境。单细胞分析确定了驻留巨噬细胞分泌的增殖信号，其中包括细胞因子烟酰胺磷酸核糖转移酶（Nampt，在人类中也称为内脂素或前B细胞克隆增强因子）。巨噬细胞微环境分泌的Nampt是肌肉再生所必需的，它通过肌肉干细胞上表达的C-C基序趋化因子受体5（Ccr5）发挥作用。该分析表明，特定巨噬细胞群体除了具有调节免疫反应的能力外，还提供了一个短暂的干细胞激活微环境，直接提供诱导增殖的信号，控制由肌肉干细胞介导的修复过程。这项研究表明，巨噬细胞来源的肌肉干细胞微环境信号，如NAMPT，可作为骨骼肌损伤和疾病的新型治疗手段。
