Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality
Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality
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DOI：
10.1016/j.celrep.2021.109223
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发表时间：
2021-06-08
期刊：
影响因子：
8.8
通讯作者：
von Maltzahn, Julia
中科院分区：
文献类型：
--
作者：
Schuler, Svenja C.;Kirkpatrick, Joanna M.;von Maltzahn, Julia
在衰老过程中，由于肌肉干细胞（MuSC）的内在变化及其生态位的改变，骨骼肌的再生能力下降。在这里，我们使用定量质谱来表征 MuSC 蛋白质组的内在变化以及衰老过程中 MuSC 生态位的重塑。我们生成了一个网络，连接位于微环境中受年龄影响的配体和 MuSC 上的细胞表面受体。因此，我们揭示了整合素、Lrp1、Egfr 和 Cd44 的信号传导是随着衰老而受到干扰的主要细胞通讯轴。我们研究了 Smoc2 的作用，Smoc2 是一种随着衰老而积累的分泌蛋白，主要源自纤维脂肪祖细胞。 Smoc2 水平升高会导致衰老过程中观察到的异常整合素 beta-1 (Itgb1)/丝裂原激活蛋白激酶 (MAPK) 信号传导，从而导致 MuSC 功能和肌肉再生受损。通过将 MuSC 蛋白质组的变化与其生态位的改变联系起来，我们的工作将能够更好地了解 MuSC 在衰老过程中如何受到影响。
During aging, the regenerative capacity of skeletal muscle decreases due to intrinsic changes in muscle stem cells (MuSCs) and alterations in their niche. Here, we use quantitative mass spectrometry to characterize intrinsic changes in the MuSC proteome and remodeling of the MuSC niche during aging. We generate a network connecting age-affected ligands located in the niche and cell surface receptors on MuSCs. Thereby, we reveal signaling by integrins, Lrp1, Egfr, and Cd44 as the major cell communication axes perturbed through aging. We investigate the effect of Smoc2, a secreted protein that accumulates with aging, primarily originating from fibro-adipogenic progenitors. Increased levels of Smoc2 contribute to the aberrant Integrin beta-1 (Itgb1)/mitogen-activated protein kinase (MAPK) signaling observed during aging, thereby causing impaired MuSC functionality and muscle regeneration. By connecting changes in the proteome of MuSCs to alterations of their niche, our work will enable a better understanding of how MuSCs are affected during aging.