Modulation of human embryonic stem cell-derived cardiomyocyte growth: a testbed for studying human cardiac hypertrophy?
Modulation of human embryonic stem cell-derived cardiomyocyte growth: a testbed for studying human cardiac hypertrophy?
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DOI：
10.1016/j.yjmcc.2010.10.029
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发表时间：
2011-02
影响因子：
5
通讯作者：
Harding SE
中科院分区：
文献类型：
--
作者：
Földes G;Mioulane M;Wright JS;Liu AQ;Novak P;Merkely B;Gorelik J;Schneider MD;Ali NN;Harding SE
人类胚胎干细胞来源的心肌细胞（hESC-CM）正在被开发用于组织修复和心脏生理学和病理生理学的模型系统。然而，它们生长的信号要求尚未得到充分表征。我们发现，hESC-CM在长期培养中保持了体积增加的能力。将hESC-CM暴露于等轴循环拉伸、血管紧张素II和苯肾上腺素（PE）等肥厚刺激下，细胞大小和体积、hESC-CM有组织肌瘤的百分比、ANF水平和细胞骨架组装增加。PE对细胞大小的影响与对细胞周期的影响是可分离的。p38-MAPK、钙调磷酸酶/FKBP和mTOR阻滞剂完全抑制PE引起的细胞大小变化。p38-MAPK和钙调磷酸酶也与基底细胞生长有关。ERK、JNK和CaMK II抑制剂部分降低PE效应；PKG或GSK3β抑制剂无影响。p38-MAPK的作用被一种额外的药理学抑制剂和腺病毒感染hESC-CM的p38-MAPK的显性抑制形式证实。上游MAP2K3b具有组成性活性的hESC-CM感染导致细胞大小增加，肉瘤和细胞骨架组装增加，细胞伸长，并诱导ANF mRNA水平。siRNA敲低p38-MAPK抑制pe诱导的细胞大小效应。这些结果揭示了活性蛋白激酶信号在hESC-CM生长和肥大中的重要作用，这可能意味着hESC-CM作为一种新的体外测试系统。这篇文章是题为“心血管干细胞重访”的特刊的一部分。►人类胚胎干细胞衍生的心肌细胞体积增大。它们的生长受到经典的生理和病理肥厚因子的刺激。许多肥厚通路在这一过程中起作用，包括p38-MAPK、钙调磷酸酶、FKBP、mTOR、HDAC II、ERK、JNK和CAMK II。细胞生长调控和细胞周期进程是可分离的过程。这些细胞的发展可以成为心脏研究人员或制药行业的工具。
Human embryonic stem cell-derived cardiomyocytes (hESC-CM) are being developed for tissue repair and as a model system for cardiac physiology and pathophysiology. However, the signaling requirements of their growth have not yet been fully characterized. We showed that hESC-CM retain their capacity for increase in size in long-term culture. Exposing hESC-CM to hypertrophic stimuli such as equiaxial cyclic stretch, angiotensin II, and phenylephrine (PE) increased cell size and volume, percentage of hESC-CM with organized sarcomeres, levels of ANF, and cytoskeletal assembly. PE effects on cell size were separable from those on cell cycle. Changes in cell size by PE were completely inhibited by p38–MAPK, calcineurin/FKBP, and mTOR blockers. p38–MAPK and calcineurin were also implicated in basal cell growth. Inhibitors of ERK, JNK, and CaMK II partially reduced PE effects; PKG or GSK3β inhibitors had no effect. The role of p38–MAPK was confirmed by an additional pharmacological inhibitor and adenoviral infection of hESC-CM with a dominant-inhibitory form of p38–MAPK. Infection of hESC-CM with constitutively active upstream MAP2K3b resulted in an increased cell size, sarcomere and cytoskeletal assembly, elongation of the cells, and induction of ANF mRNA levels. siRNA knockdown of p38–MAPK inhibited PE-induced effects on cell size. These results reveal an important role for active protein kinase signaling in hESC-CM growth and hypertrophy, with potential implications for hESC-CM as a novel in vitro test system. This article is part of a special issue entitled, "Cardiovascular Stem Cells Revisited". ► Human embryonic stem cell-derived cardiomyocytes increase in size. ► Their growth is stimulated by classical physiological and pathological hypertrophic agents. ► A number of hypertrophic pathways act in this process, including p38–MAPK, calcineurin, FKBP, mTOR, HDAC II, ERK, JNK, and CAMK II. ► The regulation of cell growth and cell cycle progression are separable processes. ► The development of the cells can be a tool for the cardiac researcher or pharmaceutical industry.
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影响因子：
64.5
作者：
Park IH;Arora N;Huo H;Maherali N;Ahfeldt T;Shimamura A;Lensch MW;Cowan C;Hochedlinger K;Daley GQ
通讯作者：
Daley GQ
影响因子：
48
作者：
Novak, Pavel;Li, Chao;Shevchuk, Andrew I.;Stepanyan, Ruben;Caldwell, Matthew;Hughes, Simon;Smart, Trevor G.;Gorelik, Julia;Ostanin, Victor P.;Lab, Max J.;Moss, Guy W. J.;Frolenkov, Gregory I.;Klenerman, David;Korchev, Yuri E.
通讯作者：
Korchev, Yuri E.
影响因子：
3.7
作者：
GAUB, J;AUER, G;ZETTERBERG, A
通讯作者：
ZETTERBERG, A
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.2
作者：
Aouadi, Myriam;Bost, Frederic;Binetruy, Bernard
通讯作者：
Binetruy, Bernard