Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice.
Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice.
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DOI：
10.1038/nm.4126
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发表时间：
2016-08
期刊：
影响因子：
82.9
通讯作者：
Bentzinger CF
中科院分区：
文献类型：
--
作者：
Lukjanenko L;Jung MJ;Hegde N;Perruisseau-Carrier C;Migliavacca E;Rozo M;Karaz S;Jacot G;Schmidt M;Li L;Metairon S;Raymond F;Lee U;Sizzano F;Wilson DH;Dumont NA;Palini A;Fässler R;Steiner P;Descombes P;Rudnicki MA;Fan CM;von Maltzahn J;Feige JN;Bentzinger CF
长期以来，人们一直认为，与年龄相关的利基变化会损害体细胞的功能。在这里，我们证明了骨骼肌中老化的干细胞生态位含有显著降低的纤维连接蛋白(FN)水平，导致肌肉干细胞(MuSCs)的功能和维持的不利后果。从年轻的再生肌肉中删除编码FN的基因会复制衰老的表型，并导致MUSC数量的损失。通过细胞外基质(ECM)文库筛选和路径分析，我们确定FN是MuSCs的首选黏附底物，并证明整合素经粘着斑激酶和p38丝裂原活化蛋白激酶途径介导的信号在老年小鼠的MuSCs中被强烈去调节，原因是与NICE的黏附不足。老年壁龛中FN水平的重建可以重新动员干细胞，恢复年轻时的肌肉再生。综上所述，我们认为干细胞在NICE ECM中与FN的黏附丧失是一种以前未知的衰老机制。
Age-related changes in the niche have long been postulated to impair the function of somatic stem cells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism.