THE REQUIREMENT FOR β1-INTEGRIN IN THE MUSCLE STEM CELL NICHE

[摘要] Interactions between stem cells and their microenvironment, or niche, are essential for their maintenance and function.The adult muscle stem cell, i.e. the satellite cell (SC), is maintained in a quiescent state. Muscle damage, followed by release of numerous factors including fibroblast growth factor (FGF), leads to SC activation for muscle regeneration.Aged SCs have reduced regeneration capacity as they are insensitive to FGF for self-renewal, but what underlies this defect is unknown. Utilizing a satellite cell specific Cre/loxP drive to ablate β1-integrin specifically in the adult SC, I show that β1-integrin is the sensor of the SC niche. β1-integrin deficient young SCs lose their quiescence and their ability to sustain muscle regeneration. Here I describe a phenotype reminiscent of the Pax7-/- mice, demonstrating the importance for β1-integrin in maintaining the stem cell fate. Satellite cells that have lost integrin commit to differentiation at the expense of renewal, and secondarily are deficient in fusion. Interestingly, these properties are reminiscent of aged SCs. Noting these similarities, I further investigated the β1-integrin activity and function in aged satellite cells. I show that aged SCs display aberrant patterns of active β1-integrin and its effectors, revealing their dysregulation. By enhancing β1-integrin activation in aged SCs, self-renewal is restored by rescuing sensitivity to FGF in vitro and muscle regenerative capacity in vivo. These results show β1-integrin senses the SC niche to maintain responsiveness to FGF, and provides potential therapeutics for age-related muscle decline.

[发布机构] Johns Hopkins University

[效力级别] Cell Biology

[关键词] Stem Cell;Cell Biology;Extracellular Matrix;Muscular Dystrophies;Biology