Stem cells transform into a cardiac phenotype with remodeling of the nuclear transport machinery.
Stem cells transform into a cardiac phenotype with remodeling of the nuclear transport machinery.
复制标题
DOI：
10.1038/ncpcardio0763
复制
发表时间：
2007-02-01
影响因子：
--
通讯作者：
Terzic, Andre
中科院分区：
文献类型：
--
作者：
Perez-Terzic, Carmen;Faustino, Randolph S;Terzic, Andre
转录因子的核转运是干细胞定向分化为组织特异性谱系的关键步骤。虽然核孔是核质交换的守门人，但核转运机制如何能够支持遗传重编程和细胞分化尚不清楚。在这里，我们报告了胚胎干细胞心肌分化过程中核转运因子表达和核孔显微解剖的动态变化。来自多能干细胞的心脏后代显示出独特的蛋白质组学特征，其特征在于心脏特异性蛋白质的出现。这与心脏转录因子的核转位有关。核转运基因，包括核孔蛋白，importins，exportins，transportins和RAN相关因子，在基因组水平上被全面下调，简化了干细胞衍生的心脏发生的分化程序。心脏分子表型的建立与跨越核膜的核孔密度增加有关。在纳米级分辨率下，单个核孔表现出构象变化，导致孔径扩大和导管占用的可能性增加。因此，胚胎干细胞经历与心脏转录因子的核转位和心源性程序的执行相关的核运输基础结构的适应性重塑，强调了核质运输机制在适应分化要求方面的可塑性。
Nuclear transport of transcription factors is a critical step in stem cell commitment to a tissue-specific lineage. While it is recognized that nuclear pores are gatekeepers of nucleocytoplasmic exchange, it is unknown how the nuclear transport machinery becomes competent to support genetic reprogramming and cell differentiation. Here, we report the dynamics of nuclear transport factor expression and nuclear pore microanatomy during cardiac differentiation of embryonic stem cells. Cardiac progeny derived from pluripotent stem cells displayed a distinct proteomic profile characterized by the emergence of cardiac-specific proteins. This profile correlated with the nuclear translocation of cardiac transcription factors. The nuclear transport genes, including nucleoporins, importins, exportins, transportins, and Ran-related factors, were globally downregulated at the genomic level, streamlining the differentiation program underlying stem cell-derived cardiogenesis. Establishment of the cardiac molecular phenotype was associated with an increased density of nuclear pores spanning the nuclear envelope. At nanoscale resolution, individual nuclear pores exhibited conformational changes resulting in the expansion of the pore diameter and an augmented probability of conduit occupancy. Thus, embryonic stem cells undergo adaptive remodeling of the nuclear transport infrastructure associated with nuclear translocation of cardiac transcription factors and execution of the cardiogenic program, underscoring the plasticity of the nucleocytoplasmic trafficking machinery in accommodating differentiation requirements.