Notch1 regulates the fate of cardiac progenitor cells (Retracted Article)
Notch1 regulates the fate of cardiac progenitor cells (Retracted Article)
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DOI：
10.1073/pnas.0808357105
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发表时间：
2008-10-07
影响因子：
11.1
通讯作者：
Leri, Annarosa
中科院分区：
文献类型：
--
作者：
Boni, Alessandro;Urbanek, Konrad;Leri, Annarosa
Notch受体介导多个器官中的细胞命运决定。在目前的工作中，我们验证了Nkx2.5是Notch 1的靶基因的假设，并提出了Notch 1调节成人心脏中肌细胞定型的可能性。小生境中的心脏祖细胞（CPC）表达Notch 1受体，支持细胞显示Notch配体Jagged 1。Notch 1胞内结构域核转位（N1 ICD）上调CPC中的Nkx2.5并促进体外循环心肌细胞的形成。N1 ICD和RBP-Jk形成蛋白质复合物，该蛋白质复合物进而结合Nkx2.5启动子，启动转录和肌细胞分化。相反，血管细胞的转录因子下调Jagged 1激活Notch 1途径。重要的是，在梗死小鼠中抑制Notch 1会损害常驻CPC对肌细胞谱系的承诺，从而对抗心肌发生。这些观察结果表明，Notch 1有利于早期指定的CPC的肌细胞表型，但保持新形成的细胞在一个高度增殖的状态。分裂的Nkx2.5阳性肌细胞对应于转运放大细胞，其调节心脏的复制能力。总之，Notch 1可能对心脏稳态的控制及其对病理状态的适应具有关键影响。
The Notch receptor mediates cell fate decision in multiple organs. in the current work we tested the hypothesis that Nkx2.5 is a target gene of Notch1 and raised the possibility that Notch1 regulates myocyte commitment in the adult heart. Cardiac progenitor cells (CPCs) in the niches express Notch1 receptor, and the supporting cells exhibit the Notch ligand Jagged1. The nuclear translocation of Notch1 intracellular domain (N1ICD) up-regulates Nkx2.5 in CPCs and promotes the formation of cycling myocytes in vitro. N1ICD and RBP-Jk form a protein complex, which in turn binds to the Nkx2.5 promoter initiating transcription and myocyte differentiation. In contrast, transcription factors of vascular cells are down-regulated by Jagged1 activation of the Notch1 pathway. Importantly, inhibition of Notch1 in infarcted mice impairs the commitment of resident CPCs to the myocyte lineage opposing cardiomyogenesis. These observations indicate that Notch1 favors the early specification of CPCs to the myocyte phenotype but maintains the newly formed cells in a highly proliferative state. Dividing Nkx2.5-positive myocytes correspond to transit amplifying cells, which condition the replicative capacity of the heart. In conclusion, Notch1 may have critical implications in the control of heart homeostasis and its adaptation to pathologic states.