小柯机器人

美国德克萨斯大学西南医学中心Hesham A. Sadek小组近期取得新进展。他们发现了钙调神经磷酸酶–Hoxb13通路调节哺乳动物心肌细胞的生长方式。2020年4月22日，《自然》杂志在线发表了这一成果。

研究人员发现在产后心肌细胞中Hoxb13可以作为Meis1（一种三氨基酸环延伸（TALE）家族同源结构域转录因子）的辅因子。心肌细胞Hoxb13特异性缺失可以延长出生后心肌细胞增殖的窗口并重新激活成年心脏中心肌细胞的周期。而且，成年心脏Meis1-Hoxb13双敲除具有广泛的心肌细胞有丝分裂、肌节拆卸和心肌梗死后左心室收缩功能的改善，正如超声心动图和磁共振成像所证实的那样。

此外，染色质免疫沉淀-测序表明Meis1和Hoxb13协同作用来调节心肌细胞的成熟和细胞周期。最后，研究人员发现钙粒子激活的蛋白磷酸酶-钙调神经磷酸酶介导了Hoxb13 204位丝氨酸的脱磷酸，导致其入核和细胞周期停滞。这些结果表明，Meis1和Hoxb13协同作用来调节心肌细胞的成熟和增殖，这为增生性和肥大性心肌细胞之间联系的机制提供了见解。

据了解，造成人心力衰竭的主要因素是成年心脏在受伤后无法自行修复。最近研究证明，产后早期的哺乳动物心脏在受到损伤后能够通过已有心肌细胞的增殖而再生，并且Meis1在出生后转移至心肌细胞核并介导产后细胞周期停滞。

附：英文原文

Title: A calcineurin–Hoxb13 axis regulates growth mode of mammalian cardiomyocytes

Author: Ngoc Uyen Nhi Nguyen, Diana C. Canseco, Feng Xiao, Yuji Nakada, Shujuan Li, Nicholas T. Lam, Shalini A. Muralidhar, Jainy J. Savla, Joseph A. Hill, Victor Le, Kareem A. Zidan, Hamed W. El-Feky, Zhaoning Wang, Mahmoud Salama Ahmed, Maimon E. Hubbi, Ivan Menendez-Montes, Jesung Moon, Shah R. Ali, Victoria Le, Elisa Villalobos, Magid S. Mohamed, Waleed M. Elhelaly, Suwannee Thet, Chukwuemeka George Anene-Nzelu, Wilson Lek Wen Tan, Roger S. Foo, Xun Meng, Mohammed Kanchwala, Chao Xing, Jagoree Roy, Martha S. Cyert, Beverly A. Rothermel, Hesham A. Sadek

Issue&Volume: 2020-04-22

Abstract: A major factor in the progression to heart failure in humans is the inability of the adult heart to repair itself after injury. We recently demonstrated that the early postnatal mammalian heart is capable of regeneration following injury through proliferation of preexisting cardiomyocytes1,2 and that Meis1, a three amino acid loop extension (TALE) family homeodomain transcription factor, translocates to cardiomyocyte nuclei shortly after birth and mediates postnatal cell cycle arrest3. Here we report that Hoxb13 acts as a cofactor of Meis1 in postnatal cardiomyocytes. Cardiomyocyte-specific deletion of Hoxb13 can extend the postnatal window of cardiomyocyte proliferation and reactivate the cardiomyocyte cell cycle in the adult heart. Moreover, adult Meis1–Hoxb13 double-knockout hearts display widespread cardiomyocyte mitosis, sarcomere disassembly and improved left ventricular systolic function following myocardial infarction, as demonstrated by echocardiography and magnetic resonance imaging. Chromatin immunoprecipitation with sequencing demonstrates that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and cell cycle. Finally, we show that the calcium-activated protein phosphatase calcineurin dephosphorylates Hoxb13 at serine-204, resulting in its nuclear localization and cell cycle arrest. These results demonstrate that Meis1 and Hoxb13 act cooperatively to regulate cardiomyocyte maturation and proliferation and provide mechanistic insights into the link between hyperplastic and hypertrophic growth of cardiomyocytes.

DOI: 10.1038/s41586-020-2228-6

Source: https://www.nature.com/articles/s41586-020-2228-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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