Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart
Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart
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DOI：
10.1038/nature14582
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发表时间：
2015-07-09
期刊：
影响因子：
64.8
通讯作者：
Sadek, Hesham A.
中科院分区：
文献类型：
--
作者：
Kimura, Wataru;Xiao, Feng;Sadek, Hesham A.
尽管成年哺乳动物心脏在大量心肌细胞损失后不能进行有意义的功能恢复，但现在清楚的是，成年小鼠和人类心脏中发生了适度的心肌细胞更新（1，2），主要由预先存在的心肌细胞增殖介导（3-5）。然而，由于缺乏可识别的遗传标记，迄今为止还不可能对这些循环心肌细胞进行命运作图（6）。在几个器官中，干细胞或祖细胞存在于相对缺氧的微环境中，其中缺氧诱导因子1 α（Hif-1 α）亚基的稳定对其维持和功能至关重要（7-10）。在这里，我们报告的命运映射缺氧细胞及其后代通过产生一个转基因小鼠表达嵌合蛋白，其中氧依赖性降解（ODD）结构域的HIF-1 α融合到他莫昔芬诱导的CreERT 2重组酶。在携带由普遍存在的CAG启动子或心肌细胞特异性肌球蛋白重链启动子驱动的creERT 2-ODD转基因的小鼠中，我们鉴定了一种罕见的缺氧心肌细胞群体，其显示出增殖性新生心肌细胞的特征，例如较小的尺寸，单核化和较低的氧化DNA损伤。值得注意的是，这些缺氧心肌细胞广泛地促进了成年心脏中新心肌细胞的形成。这些结果表明，缺氧信号是一个重要的标志，循环心肌细胞，并建议缺氧命运映射可以是一个强大的工具，用于确定在成年哺乳动物的循环细胞。
Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts(1,2), mediated primarily by proliferation of pre-existing cardiomyocytes(3-5). However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers(6). In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1 alpha) subunit is critical for their maintenance and function(7-10). Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1 alpha is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the cardiomyocyte-specific a myosin heavy chain promoter, we identify a rare population of hypoxic cardiomyocytes that display characteristics of proliferative neonatal cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic cardiomyocytes contributed widely to new cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals.