C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway.
C3orf58, a novel paracrine protein, stimulates cardiomyocyte cell-cycle progression through the PI3K-AKT-CDK7 pathway.
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DOI：
10.1161/circresaha.113.301075
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发表时间：
2013-08-02
影响因子：
20.1
通讯作者：
Dzau VJ
中科院分区：
文献类型：
--
作者：
Beigi F;Schmeckpeper J;Pow-Anpongkul P;Payne JA;Zhang L;Zhang Z;Huang J;Mirotsou M;Dzau VJ
心脏的再生能力在出生后不久就明显减弱，这与心肌细胞从细胞周期中全面退出相一致。因此，成年哺乳动物心脏在损伤后再生的能力有限。因此，发现能够诱导心肌细胞增殖的因子引起了高度兴趣，并且在过去几年中一直是广泛研究的焦点。我们最近鉴定了C3 orf 58作为一种新的缺氧和Akt诱导的干细胞因子（HASF），其由间充质干细胞分泌，可以通过细胞保护机制促进心脏修复。在这里，我们测试了HASF也可以通过刺激心肌细胞分裂和增殖促进心脏再生的假设。用纯化的重组HASF蛋白在培养物中刺激新生心室心肌细胞7天。与对照未处理的细胞相比，HASF处理的新生心肌细胞表现出60%的DNA合成增加，通过BrdU掺入测量。免疫荧光共聚焦显微镜证实了这些结果，显示有丝分裂和胞质分裂期心肌细胞数量增加了50-100%。重要的是，在转基因小鼠模型中HASF的体内心脏过表达导致新生儿和成年心肌细胞中DNA合成和胞质分裂水平提高。这些增殖作用由PI 3 K-AKT-CDK 7途径调节，如通过使用PI 3 K途径特异性抑制剂和Cdk 7基因沉默所揭示的。我们的研究支持HASF通过PI 3 K-AKT-CDK 7途径诱导心肌细胞增殖的假设。这一发现可能对心脏再生生物学和治疗学具有重要意义。
The regenerative capacity of the heart is markedly diminished shortly after birth coinciding with overall withdrawal of cardiomyocytes from cell cycle. Consequently, the adult mammalian heart has limited capacity to regenerate after injury. The discovery of factors that can induce cardiomyocyte proliferation is therefore of high interest and has been the focus of extensive investigation over the past years. We have recently identified C3orf58 as a novel Hypoxia and Akt induced Stem cell Factor (HASF) secreted from mesenchymal stem cells that can promote cardiac repair through cytoprotective mechanisms. Here, we tested the hypothesis that HASF can also contribute to cardiac regeneration by stimulating cardiomyocyte division and proliferation. Neonatal ventricular cardiomyocytes were stimulated in culture for seven days with purified recombinant HASF protein. Compared to control untreated cells, HASF-treated neonatal cardiomyocytes exhibited 60% increase in DNA synthesis as measured by BrdU incorporation. These results were confirmed by immunofluorescence confocal microscopy showing a 50–100% increase in the number of cardiomyocytes in the mitotic and cytokinesis phases. Importantly, in vivo cardiac overexpression of HASF in a transgenic mouse model resulted in enhanced level of DNA synthesis and cytokinesis in neonatal and adult cardiomyocytes. These proliferative effects were modulated by a PI3K-AKT-CDK7 pathway as revealed by the use of PI3K pathway specific inhibitors and silencing of the Cdk7 gene. Our studies support the hypothesis that HASF induces cardiomyocyte proliferation via a PI3K-AKT-CDK7 pathway. The implications of this finding may be significant for cardiac regeneration biology and therapeutics.