Adamowicz Martyna, Morgan Claire C, Haubner Bernhard J, Noseda Michela, Collins Melissa J, Abreu Paiva Marta, Srivastava Prashant K, Gellert Pascal, Razzaghi Bonnie, O'Gara Peter, Raina Priyanka, Game Laurence, Bottolo Leonardo, Schneider Michael D, Harding Sian E, Penninger Josef, Aitman Timothy J
From the Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland, United Kingdom (T.J.A.); National Heart and Lung Institute (M.A., C.C.M., M.N., M.A.P., P.O., M.D.S., S.E.H.), Department of Medicine (C.C.M., M.J.C., P.K.S., B.R., P.R., T.J.A.), Department of Mathematics (L.B.), Imperial College London, United Kingdom; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria (B.J.H., J.P.); Department of Internal Medicine III, Medical University of Innsbruck, Austria (B.J.H.); and Physiological Genomics and Medicine (P.G.), Genomics Core Laboratory (L.G.), MRC Clinical Sciences Centre, London, United Kingdom.
Circ Genom Precis Med. 2018 Feb;11(2):e001805. doi: 10.1161/CIRCGEN.117.001805. Epub 2018 Feb 1.
The adult mammalian heart has little regenerative capacity after myocardial infarction (MI), whereas neonatal mouse heart regenerates without scarring or dysfunction. However, the underlying pathways are poorly defined. We sought to derive insights into the pathways regulating neonatal development of the mouse heart and cardiac regeneration post-MI.
Total RNA-seq of mouse heart through the first 10 days of postnatal life (referred to as P3, P5, P10) revealed a previously unobserved transition in microRNA (miRNA) expression between P3 and P5 associated specifically with altered expression of protein-coding genes on the focal adhesion pathway and cessation of cardiomyocyte cell division. We found profound changes in the coding and noncoding transcriptome after neonatal MI, with evidence of essentially complete healing by P10. Over two-thirds of each of the messenger RNAs, long noncoding RNAs, and miRNAs that were differentially expressed in the post-MI heart were differentially expressed during normal postnatal development, suggesting a common regulatory pathway for normal cardiac development and post-MI cardiac regeneration. We selected exemplars of miRNAs implicated in our data set as regulators of cardiomyocyte proliferation. Several of these showed evidence of a functional influence on mouse cardiomyocyte cell division. In addition, a subset of these miRNAs, miR-144-3p, miR-195a-5p, miR-451a, and miR-6240 showed evidence of functional conservation in human cardiomyocytes.
The sets of messenger RNAs, miRNAs, and long noncoding RNAs that we report here merit further investigation as gatekeepers of cell division in the postnatal heart and as targets for extension of the period of cardiac regeneration beyond the neonatal period.
成年哺乳动物心脏在心肌梗死（MI）后再生能力有限，而新生小鼠心脏能无瘢痕或功能障碍地再生。然而，其潜在机制尚不清楚。我们试图深入了解调节小鼠心脏新生儿期发育及MI后心脏再生的途径。
对出生后前10天（称为P3、P5、P10）的小鼠心脏进行全RNA测序，揭示了在P3和P5之间微小RNA（miRNA）表达存在此前未观察到的转变，这与粘着斑途径上蛋白质编码基因表达的改变以及心肌细胞分裂的停止特异性相关。我们发现新生期MI后编码和非编码转录组发生了深刻变化，到P10时有基本完全愈合的证据。MI后心脏中差异表达的信使RNA、长链非编码RNA和miRNA中，超过三分之二在正常出生后发育过程中也有差异表达，这表明正常心脏发育和MI后心脏再生存在共同的调控途径。我们从数据集中选择了一些涉及心肌细胞增殖调节的miRNA示例。其中一些显示出对小鼠心肌细胞分裂有功能影响的证据。此外，这些miRNA中的一部分，即miR-144-3p、miR-195a-5p、miR-451a和miR-6240，在人类心肌细胞中显示出功能保守的证据。
我们在此报告的信使RNA、miRNA和长链非编码RNA集合，作为出生后心脏细胞分裂的守门人以及将心脏再生期延长至新生儿期之后的靶点，值得进一步研究。
