Redox-dependent BMI1 activity drives in vivo adult cardiac progenitor cell differentiation
Redox-dependent BMI1 activity drives in vivo adult cardiac progenitor cell differentiation
复制标题
DOI：
10.1038/s41418-017-0022-2
复制
发表时间：
2018-03-01
影响因子：
12.4
通讯作者：
Bernad, Antonio
中科院分区：
文献类型：
--
作者：
Herrero, Diego;Tome, Maria;Bernad, Antonio
活性氧簇（ROS）的积累与几种心血管疾病和细胞周期退出的哺乳动物心肌细胞，一个关键的限制因素，在成年哺乳动物心脏的再生能力。多梳复合物组分BMI1与成体祖细胞相连，是DNA修复和氧化还原调节的重要伙伴。我们发现高BMI1表达与低ROS水平的成年Sca1（+）心脏祖细胞亚群相关。在体内平衡中，BMI1抑制细胞命运基因，包括心源性分化程序。然而，氧化损伤通过去抑制典型靶基因而改变了体内BMI1活性，从而有利于其抗氧化和抗胚泡生成功能。然而，这种氧化还原介导的机制并不局限于损伤情况，我们报告了稳定状态下ROS相关的心脏祖细胞分化。这些发现表明氧化还原状态如何影响心脏祖细胞反应，并确定氧化还原介导的BMI1调节与体内细胞身份维持的影响。
Accumulation of reactive oxygen species (ROS) is associated with several cardiovascular pathologies and with cell cycle exit by neonanatal cardiomyocytes, a key limiting factor in the regenerative capacity of the adult mammalian heart. The polycomb complex component BMI1 is linked to adult progenitors and is an important partner in DNA repair and redox regulation. We found that high BMI1 expression is associated with an adult Sca1(+) cardiac progenitor sub-population with low ROS levels. In homeostasis, BMI1 repressed cell fate genes, including a cardiogenic differentiation program. Oxidative damage nonetheless modified BMI1 activity in vivo by derepressing canonical target genes in favor of their antioxidant and anticlastogenic functions. This redox-mediated mechanism is not restricted to damage situations, however, and we report ROS-associated differentiation of cardiac progenitors in steady state. These findings demonstrate how redox status influences the cardiac progenitor response, and identify redox-mediated BMI1 regulation with implications in maintenance of cellular identity in vivo.