Mechanosensitive kinases regulate stiffness-induced cardiomyocyte maturation.
Mechanosensitive kinases regulate stiffness-induced cardiomyocyte maturation.
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DOI：
10.1038/srep06425
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发表时间：
2014-09-19
影响因子：
4.6
通讯作者：
Engler AJ
中科院分区：
文献类型：
--
作者：
Young JL;Kretchmer K;Ondeck MG;Zambon AC;Engler AJ
细胞在整个发育过程中分泌和组装细胞外基质，从而产生时间依赖性的组织特异性僵硬。与静态水凝胶相比，水凝胶系统模拟心肌基质硬化，即在1周内增加约10倍，可增强胚胎心肌细胞的肌原纤维组织，因此我们试图确定相关的特异性机械敏感蛋白。研究了309种独特蛋白激酶在胚胎心肌细胞中的表达和/或磷酸化状态，这些蛋白激酶分别涂在动态硬化或静态成熟心肌硬化水凝胶上。这些激酶的基因本体论分析发现，在动态与静态基质（包括PI3K/AKT和p38 MAPK）上表现出时间依赖性的上调，而已知的心肌细胞成熟拮抗剂GSK3β则下调。此外，在静态基质上抑制GSK3β可改善肌原纤维的自发收缩和组织，而在动态基质上抑制激动剂AKT可减少肌原纤维的组织和自发收缩，证实其在机械驱动成熟中的作用。综上所述，这些数据表明，机械驱动的成熟至少部分是通过在局灶粘连处的主动机械感应实现的，影响了多种对心肌形成重要的蛋白激酶的表达和磷酸化。
Cells secrete and assemble extracellular matrix throughout development, giving rise to time-dependent, tissue-specific stiffness. Mimicking myocardial matrix stiffening, i.e. ~10-fold increase over 1 week, with a hydrogel system enhances myofibrillar organization of embryonic cardiomyocytes compared to static hydrogels, and thus we sought to identify specific mechanosensitive proteins involved. Expression and/or phosphorylation state of 309 unique protein kinases were examined in embryonic cardiomyocytes plated on either dynamically stiffening or static mature myocardial stiffness hydrogels. Gene ontology analysis of these kinases identified cardiogenic pathways that exhibited time-dependent up-regulation on dynamic versus static matrices, including PI3K/AKT and p38 MAPK, while GSK3β, a known antagonist of cardiomyocyte maturation, was down-regulated. Additionally, inhibiting GSK3β on static matrices improved spontaneous contraction and myofibril organization, while inhibiting agonist AKT on dynamic matrices reduced myofibril organization and spontaneous contraction, confirming its role in mechanically-driven maturation. Together, these data indicate that mechanically-driven maturation is at least partially achieved via active mechanosensing at focal adhesions, affecting expression and phosphorylation of a variety of protein kinases important to cardiomyogenesis.
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影响因子：
7.7
作者：
Holle, Andrew W.;Engler, Adam J.
通讯作者：
Engler, Adam J.
影响因子：
2.4
作者：
Jacot JG;Martin JC;Hunt DL
通讯作者：
Hunt DL
DOI：
10.1126/science.1171643
发表时间：
2009-06-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Discher DE;Mooney DJ;Zandstra PW
通讯作者：
Zandstra PW
DOI：
10.1083/jcb.200503155
发表时间：
2005-12-19
期刊：
The Journal of cell biology
影响因子：
--
作者：
Alon R;Feigelson SW;Manevich E;Rose DM;Schmitz J;Overby DR;Winter E;Grabovsky V;Shinder V;Matthews BD;Sokolovsky-Eisenberg M;Ingber DE;Benoit M;Ginsberg MH
通讯作者：
Ginsberg MH
影响因子：
4.9
作者：
Bajaj, Piyush;Tang, Xin;Bashir, Rashid
通讯作者：
Bashir, Rashid