Aging Disrupts Muscle Stem Cell Function by Impairing Matricellular WISP1 Secretion from Fibro-Adipogenic Progenitors
Aging Disrupts Muscle Stem Cell Function by Impairing Matricellular WISP1 Secretion from Fibro-Adipogenic Progenitors
复制标题
DOI：
10.1016/j.stem.2018.12.014
复制
发表时间：
2019-03-07
期刊：
影响因子：
23.9
通讯作者：
Feige, Jerome N.
中科院分区：
文献类型：
--
作者：
Lukjanenko, Laura;Karaz, Sonia;Feige, Jerome N.
骨骼肌年龄相关性再生障碍的研究主要集中在肌肉干细胞（MuSC）的表型上。相比之下，衰老对MuSC生态位中调节细胞的影响在很大程度上仍未被探索。在这里，我们证明了衰老损害了小鼠成脂祖细胞（FAP）的功能，从而间接影响了MuSC的成肌潜能。使用转录组学分析，我们确定WNT1诱导信号通路蛋白1（WISP1）作为FAP衍生的基质细胞信号，在衰老过程中丢失。WISP1是有效肌肉再生所必需的，并通过Akt信号传导控制MuSC的扩增和不对称定型。年轻FAP的移植或WISP1的全身治疗恢复了老年小鼠中MuSC的生肌能力并挽救了骨骼肌再生。我们的工作确定了FAP中WISP1的丢失导致了老年骨骼肌中的MuSC功能障碍，并证明了这种机制可以靶向恢复肌生成。
Research on age-related regenerative failure of skeletal muscle has extensively focused on the phenotypes of muscle stem cells (MuSCs). In contrast, the impact of aging on regulatory cells in the MuSC niche remains largely unexplored. Here, we demonstrate that aging impairs the function of mouse fibro- adipogenic progenitors (FAPs) and thereby indirectly affects the myogenic potential of MuSCs. Using transcriptomic profiling, we identify WNT1 Inducible Signaling Pathway Protein 1 (WISP1) as a FAP-derived matricellular signal that is lost during aging. WISP1 is required for efficient muscle regeneration and controls the expansion and asymmetric commitment of MuSCs through Akt signaling. Transplantation of young FAPs or systemic treatment with WISP1 restores the myogenic capacity of MuSCs in aged mice and rescues skeletal muscle regeneration. Our work establishes that loss of WISP1 from FAPs contributes to MuSC dysfunction in aged skeletal muscles and demonstrates that this mechanism can be targeted to rejuvenate myogenesis.