Setd4 controlled quiescent c-Kit(+) cells contribute to cardiac neovascularization of capillaries beyond activation.
Setd4 controlled quiescent c-Kit(+) cells contribute to cardiac neovascularization of capillaries beyond activation.
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Setd4控制的静态c-Kit细胞有助于心脏毛细血管新生血管形成
DOI：
10.1038/s41598-021-91105-6
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发表时间：
2021-06-02
影响因子：
4.6
通讯作者：
Yang WJ
中科院分区：
文献类型：
--
作者：
Xing S;Tian JZ;Yang SH;Huang XT;Ding YF;Lu QY;Yang JS;Yang WJ
成年哺乳动物的血管以高度有序和稳定的状态存在。在缺血性心脏中，心肌血管床有限的扩张能力不能满足对氧气供应的需求，并且心肌最终遭受不可逆的损伤。内源性c-Kit+细胞的主要贡献被认为是心脏内皮细胞的发育和稳态，这表明它们在心脏缺血性损伤治疗中的靶向潜力。已知其他组织中的静止细胞有助于细胞库的长期维持，保持增殖能力，并且在激活时促进组织稳态和响应组织损伤的再生。在这里，我们提出的证据Setd 4表达静止的c-Kit+细胞群体在成年小鼠心脏起源于胚胎阶段。条件性敲除c-Kit-CreERT 2; Setd 4f/f; Rosa 26 TdTomato小鼠中的Setd 4诱导新生小鼠和成年小鼠中毛细血管的血管内皮细胞增加。我们发现Setd 4通过H4 K20 me 3催化的PI 3 K-Akt-mTOR信号通路调节c-Kit+细胞的静止。在心肌梗死损伤的小鼠中，Setd 4基因敲除导致心肌细胞凋亡减少，梗死范围缩小，心功能改善。Setd 4-Cre; Rosa 26 mT/mG小鼠中的谱系追踪显示，Setd 4+细胞有助于每个心脏谱系。总的来说，Setd 4通过H4 K20 me 3促进异染色质形成，表观遗传地控制成年心脏中的c-Kit+细胞静止。除了激活，内源性静止c-Kit+细胞能够通过毛细血管的新血管形成改善心肌梗死损伤小鼠的心脏功能。
Blood vessels in the adult mammal exist in a highly organized and stable state. In the ischemic heart, limited expansion capacity of the myocardial vascular bed cannot satisfy demands for oxygen supply and the myocardium eventually undergoes irreversible damage. The predominant contribution of endogenous c-Kit+ cells is understood to be in the development and homeostasis of cardiac endothelial cells, which suggests potential for their targeting in treatments for cardiac ischemic injury. Quiescent cells in other tissues are known to contribute to the long-term maintenance of a cell pool, preserve proliferation capacity and, upon activation, facilitate tissue homeostasis and regeneration in response to tissue injury. Here, we present evidence of a Setd4-expressing quiescent c-Kit+ cell population in the adult mouse heart originating from embryonic stages. Conditional knock-out of Setd4 in c-Kit-CreERT2;Setd4f/f;Rosa26TdTomato mice induced an increase in vascular endothelial cells of capillaries in both neonatal and adult mice. We show that Setd4 regulates quiescence of c-Kit+ cells by the PI3K-Akt-mTOR signaling pathway via H4K20me3 catalysis. In myocardial infarction injured mice, Setd4 knock-out resulted in attenuated cardiomyocyte apoptosis, decreased infarction size and improved cardiac function. Lineage tracing in Setd4-Cre;Rosa26mT/mG mice showed that Setd4+ cells contribute to each cardiac lineage. Overall, Setd4 epigenetically controls c-Kit+ cell quiescence in the adult heart by facilitating heterochromatin formation via H4K20me3. Beyond activation, endogenous quiescent c-Kit+ cells were able to improve cardiac function in myocardial infarction injured mice via the neovascularization of capillaries.
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