Shahini Aref, Rajabian Nika, Choudhury Debanik, Shahini Shahryar, Vydiam Kalyan, Nguyen Thy, Kulczyk Joseph, Santarelli Tyler, Ikhapoh Izuagie, Zhang Yali, Wang Jianmin, Liu Song, Stablewski Aimee, Thiyagarajan Ramkumar, Seldeen Kenneth, Troen Bruce R, Peirick Jennifer, Lei Pedro, Andreadis Stelios T
Bioengineering Laboratory, Department of Chemical and Biological Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
Department of Biomedical Engineering, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA.
Sci Adv. 2021 Sep 3;7(36):eabe5671. doi: 10.1126/sciadv.abe5671.
Senescence of myogenic progenitors impedes skeletal muscle regeneration. Here, we show that overexpression of the transcription factor NANOG in senescent myoblasts can overcome the effects of cellular senescence and confer a youthful phenotype to senescent cells. NANOG ameliorated primary hallmarks of cellular senescence including genomic instability, loss of proteostasis, and mitochondrial dysfunction. The rejuvenating effects of NANOG included restoration of DNA damage response via up-regulation of DNA repair proteins, recovery of heterochromatin marks via up-regulation of histones, and reactivation of autophagy and mitochondrial energetics via up-regulation of AMP-activated protein kinase (AMPK). Expression of NANOG in the skeletal muscle of a mouse model of premature aging restored the number of myogenic progenitors and induced formation of eMyHC myofibers. This work demonstrates the feasibility of reversing the effects of cellular senescence in vitro and in vivo, with no need for reprogramming to the pluripotent state.
成肌祖细胞的衰老会阻碍骨骼肌再生。在此，我们表明衰老的成肌细胞中转录因子NANOG的过表达可克服细胞衰老的影响，并赋予衰老细胞年轻的表型。NANOG改善了细胞衰老的主要特征，包括基因组不稳定、蛋白稳态丧失和线粒体功能障碍。NANOG的年轻化作用包括通过上调DNA修复蛋白恢复DNA损伤反应，通过上调组蛋白恢复异染色质标记，以及通过上调AMP激活蛋白激酶（AMPK）重新激活自噬和线粒体能量代谢。在早衰小鼠模型的骨骼肌中表达NANOG可恢复成肌祖细胞的数量并诱导eMyHC肌纤维的形成。这项工作证明了在体外和体内逆转细胞衰老影响的可行性，而无需重编程为多能状态。
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