Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis.
Adult murine cardiomyocytes exhibit regenerative activity with cell cycle reentry through STAT3 in the healing process of myocarditis.
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DOI：
10.1038/s41598-017-01426-8
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发表时间：
2017-05-03
影响因子：
4.6
通讯作者：
Fujio Y
中科院分区：
文献类型：
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作者：
Miyawaki A;Obana M;Mitsuhara Y;Orimoto A;Nakayasu Y;Yamashita T;Fukada SI;Maeda M;Nakayama H;Fujio Y
哺乳动物的心肌细胞在出生后立即失去增殖能力，限制了成年心脏损伤后的再生。然而，临床心肌炎似乎具有自我限制的组织修复特性。在这里，我们利用实验性自身免疫性心肌炎（EAM）模型研究了心肌炎恢复后心肌细胞增殖的分子机制。EAM诱导3周后（EAM3w），心肌组织出现炎症细胞浸润，心肌细胞凋亡。然而，通过EAM5w，心肌损伤明显减轻，与EAM3w细胞周期标记阳性染色的心肌细胞增加有关。心肌细胞命运图谱研究表明，增殖的心肌细胞主要来源于已有的心肌细胞。在炎症期间，心肌细胞中信号换能器和转录激活因子3 （STAT3）被强烈激活，并伴有白细胞介素-6家族细胞因子的诱导。心肌细胞特异性消融STAT3基因可抑制恢复期心肌细胞循环频率，但不影响炎症状态，导致组织修复受损和心功能障碍。最后，微阵列分析显示，STAT3基因缺失导致心肌细胞再生相关基因金属硫蛋白和聚簇蛋白的表达减少。这些数据表明，当心脏从心肌炎引起的心脏损伤中恢复时，成年哺乳动物心肌细胞通过STAT3通过细胞周期再进入恢复再生能力。
Mammalian cardiomyocytes substantially lose proliferative capacity immediately after birth, limiting adult heart regeneration after injury. However, clinical myocarditis appears to be self-limiting with tissue-reparative properties. Here, we investigated the molecular mechanisms underlying the recovery from myocarditis with regard to cardiomyocyte proliferation using an experimental autoimmune myocarditis (EAM) model. Three weeks after EAM induction (EAM3w), cardiac tissue displayed infiltration of inflammatory cells with cardiomyocyte apoptosis. However, by EAM5w, the myocardial damage was remarkably attenuated, associated with an increase in cardiomyocytes that were positively stained with cell cycle markers at EAM3w. Cardiomyocyte fate mapping study revealed that the proliferating cardiomyocytes primarily derived from pre-existing cardiomyocytes. Signal transducer and activator of transcription 3 (STAT3) was robustly activated in cardiomyocytes during inflammation, accompanied by induction of interleukin-6 family cytokines. Cardiomyocyte-specific ablation of STAT3 gene suppressed the frequency of cycling cardiomyocytes in the recovery period without influencing inflammatory status, resulting in impaired tissue repair and cardiac dysfunction. Finally, microarray analysis revealed that the expression of regeneration-related genes, metallothioneins and clusterin, in cardiomyocytes was decreased by STAT3 gene deletion. These data show that adult mammalian cardiomyocytes restore regenerative capacity with cell cycle reentry through STAT3 as the heart recovers from myocarditis-induced cardiac damage.