Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice

被引：220

作者：

Lukjanenko, Laura ^{[1
,2
]}

Jung, M. Juliane ^{[3
]}

Hegde, Nagabhooshan ^{[1
]}

Perruisseau-Carrier, Claire ^{[1
]}

Migliavacca, Eugenia ^{[1
]}

Rozo, Michelle ^{[4
]}

Karaz, Sonia ^{[1
]}

Jacot, Guillaume ^{[1
]}

Schmidt, Manuel ^{[3
]}

Li, Liangji ^{[4
]}

Metairon, Sylviane ^{[1
]}

Raymond, Frederic ^{[1
]}

Lee, Umji ^{[1
]}

Sizzano, Federico ^{[1
]}

Wilson, David H. ^{[5
,6
]}

Dumont, Nicolas A. ^{[5
,6
]}

Palini, Alessio ^{[1
]}

Faessler, Reinhard ^{[7
]}

Steiner, Pascal ^{[1
]}

Descombes, Patrick ^{[1
]}

Rudnicki, Michael A. ^{[5
,6
]}

Fan, Chen-Ming ^{[4
]}

von Maltzahn, Julia ^{[3
]}

Feige, Jerome N. ^{[1
]}

Bentzinger, C. Florian ^{[1
]}

机构：

[1] Ecole Polytech Fed Lausanne, NIHS, Campus Ecole Polytech Fed Lausanne,Innovat Pk, Lausanne, Switzerland

[2] Ecole Polytech Fed Lausanne, Doctoral Program Biotechnol & Bioengn, Lausanne, Switzerland

[3] Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany

[4] Carnegie Inst Sci, Dept Embryol, Baltimore, MD USA

[5] Ottawa Hosp, Res Inst, Regenerat Med Program, Sprott Ctr Stem Cell Res, Ottawa, ON, Canada

[6] Univ Ottawa, Fac Med, Dept Cellular & Mol Med, Ottawa, ON, Canada

[7] Max Planck Inst Biochem, Dept Mol Med, Martinsried, Germany

来源：

NATURE MEDICINE | 2016年 / 22卷 / 08期

基金：

美国国家卫生研究院;

关键词：

SELF-RENEWAL; EXTRACELLULAR-MATRIX; REJUVENATION; PROLIFERATION; STRENGTH; SURVIVAL; MOUSE; SKIN; FAK;

D O I：

10.1038/nm.4126

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：897 / +

页数：11

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