2.Tbx6 induces cardiomyocyte proliferation in postnatal and adult mouse hearts.
2.Tbx6 induces cardiomyocyte proliferation in postnatal and adult mouse hearts.
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2.Tbx6诱导出生后和成年小鼠心脏中的心肌细胞增殖。
DOI：
10.1016/j.bbrc.2019.04.087
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Ieda M.
中科院分区：
文献类型：
--
作者：
Haginiwa S;Sadahiro T;Kojima H;Isomi M;Tamura F;Kurotsu S;Tani H;Muraoka N;Miyake N;Miyake K;Fukuda K;Ieda M.
心血管疾病是全世界死亡的主要原因。哺乳动物心肌细胞（CM）在胚胎发育期间增殖，而它们在出生后基本上失去了再生能力。在出生后和成年心脏中，在心脏祖细胞或胚胎CM中表达的特定因子可激活细胞周期并诱导CM增殖。在这里，我们报告说，Tbx 6的过度表达，丰富的心脏中胚层（祖细胞），诱导出生后和成年小鼠心脏CM增殖。通过筛选24个富集于心脏祖细胞或胚胎CM的因子，我们发现只有Tbx 6可以诱导原代培养的出生后大鼠CM的CM增殖。有趣的是，它没有诱导心脏成纤维细胞的增殖。我们接下来产生了编码Tbx 6的重组腺相关病毒血清型9载体（AAV 9-Tbx 6），用于体内转导到小鼠CM中。将AAV 9-Tbx 6皮下注射到新生小鼠中诱导出生后和成年小鼠心脏中的CM增殖。从机制上讲，Tbx 6过表达上调了多种细胞周期激活因子，包括Aurkb、Mki 67、Ccna 1和Ccnb 2，并抑制了肿瘤抑制因子Rb 1。因此，Tbx 6通过修饰细胞周期调节因子的表达促进出生后和成年小鼠心脏中的CM增殖。
Cardiovascular disease is a leading cause of death worldwide. Mammalian cardiomyocytes (CMs) proliferate during embryonic development, whereas they largely lose their regenerative capacity after birth. Defined factors expressed in cardiac progenitors or embryonic CMs may activate the cell cycle and induce CM proliferation in postnatal and adult hearts. Here, we report that the overexpression of Tbx6, enriched in the cardiac mesoderm (progenitor cells), induces CM proliferation in postnatal and adult mouse hearts. By screening 24 factors enriched in cardiac progenitors or embryonic CMs, we found that only Tbx6 could induce CM proliferation in primary cultured postnatal rat CMs. Intriguingly, it did not induce the proliferation of cardiac fibroblasts. We next generated a recombinant adeno-associated virus serotype 9 vector encoding Tbx6 (AAV9-Tbx6) for transduction into mouse CMsin vivo. The subcutaneous injection of AAV9-Tbx6 into neonatal mice induced CM proliferation in postnatal and adult mouse hearts. Mechanistically, Tbx6 overexpression upregulated multiple cell cycle activators including Aurkb, Mki67, Ccna1, and Ccnb2 and suppressed the tumor suppressor Rb1. Thus, Tbx6 promotes CM proliferation in postnatal and adult mouse hearts by modifying the expression of cell cycle regulators.