Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
Department of Cardiology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennoudai, Tsukuba City, Ibaraki, 305-8575, Japan.
Biochem Biophys Res Commun. 2019 Jun 11;513(4):1041-1047. doi: 10.1016/j.bbrc.2019.04.087. Epub 2019 Apr 19.
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 CMs in 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.
心血管疾病是全球范围内主要的死亡原因。哺乳动物心肌细胞（CMs）在胚胎发育过程中增殖，而在出生后则很大程度上失去了再生能力。在心脏祖细胞或胚胎 CMs 中表达的特定因子可能会激活细胞周期并诱导出生后和成年心脏中的 CM 增殖。在这里，我们报告 Tbx6 的过表达可在出生后和成年小鼠心脏中诱导 CM 增殖。通过筛选 24 种在心脏祖细胞或胚胎 CMs 中富集的因子，我们发现只有 Tbx6 可以诱导原代培养的出生后大鼠 CMs 增殖。有趣的是，它不会诱导心肌成纤维细胞的增殖。我们接下来生成了一个编码 Tbx6 的重组腺相关病毒血清型 9 载体（AAV9-Tbx6），用于在体内转导小鼠 CMs。将 AAV9-Tbx6 皮下注射到新生小鼠中，可诱导出生后和成年小鼠心脏中的 CM 增殖。在机制上，Tbx6 的过表达上调了多个细胞周期激活物，包括 Aurkb、Mki67、Ccna1 和 Ccnb2，并抑制了肿瘤抑制因子 Rb1。因此，Tbx6 通过调节细胞周期调节剂的表达来促进出生后和成年小鼠心脏中的 CM 增殖。
