Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury.
Oxytocin promotes epicardial cell activation and heart regeneration after cardiac injury.
复制标题
DOI：
10.3389/fcell.2022.985298
复制
发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
心血管疾病（CVD）是全球死亡的主要原因之一，经常导致严重的心脏损伤以及数十亿心肌细胞和相关血管系统的损失。过去20年的关键工作表明，这些丢失的细胞可以通过心外膜（心脏最外层的间皮层）部分再生，这一过程高度概括了其在心脏发育中的作用。心脏损伤后，成熟的心外膜细胞被激活并经历上皮-间充质转化（EMT），形成心外膜衍生祖细胞（EpiPC），这是一种多能祖细胞，可以分化成几种重要的心脏谱系，包括心肌细胞和血管细胞。在哺乳动物中，单独的这一过程不足以实现显著的再生，但有可能通过给予特定的重编程因子来启动它，从而增强EpiPC功能。在这里，我们表明，催产素（OXT），下丘脑神经内分泌肽，诱导心外膜细胞增殖，EMT，和转录活性的人诱导多能干细胞（hiPSC）衍生的心外膜细胞模型。此外，我们证明了斑马鱼心脏冷冻损伤后产生的OXT，它激发了显着的心外膜激活，促进心脏再生。催产素信号对斑马鱼胚胎的心外膜发育也至关重要。当OXT信号传导通过RNA干扰被化学或遗传抑制时，上述过程显著受损。RNA测序数据表明，转化生长因子β（TGF-β）途径是OXT诱导的心外膜激活的主要介质。我们的研究首次揭示了一种进化保守的脑控制机制，诱导受损哺乳动物和斑马鱼心脏的细胞重编程和再生，这一发现可能有助于心脏损伤治疗的转化进展。
Cardiovascular disease (CVD) is one of the leading causes of mortality worldwide, and frequently leads to massive heart injury and the loss of billions of cardiac muscle cells and associated vasculature. Critical work in the last 2 decades demonstrated that these lost cells can be partially regenerated by the epicardium, the outermost mesothelial layer of the heart, in a process that highly recapitulates its role in heart development. Upon cardiac injury, mature epicardial cells activate and undergo an epithelial-mesenchymal transition (EMT) to form epicardium-derived progenitor cells (EpiPCs), multipotent progenitors that can differentiate into several important cardiac lineages, including cardiomyocytes and vascular cells. In mammals, this process alone is insufficient for significant regeneration, but it might be possible to prime it by administering specific reprogramming factors, leading to enhanced EpiPC function. Here, we show that oxytocin (OXT), a hypothalamic neuroendocrine peptide, induces epicardial cell proliferation, EMT, and transcriptional activity in a model of human induced pluripotent stem cell (hiPSC)-derived epicardial cells. In addition, we demonstrate that OXT is produced after cardiac cryoinjury in zebrafish, and that it elicits significant epicardial activation promoting heart regeneration. Oxytocin signaling is also critical for proper epicardium development in zebrafish embryos. The above processes are significantly impaired when OXT signaling is inhibited chemically or genetically through RNA interference. RNA sequencing data suggests that the transforming growth factor beta (TGF-β) pathway is the primary mediator of OXT-induced epicardial activation. Our research reveals for the first time an evolutionary conserved brain-controlled mechanism inducing cellular reprogramming and regeneration of the injured mammalian and zebrafish heart, a finding that could contribute to translational advances for the treatment of cardiac injuries.
登录
查看更多内容
DOI：
10.1186/1755-1536-5-15
发表时间：
2012-09-03
期刊：
Fibrogenesis & tissue repair
影响因子：
--
作者：
Fan D;Takawale A;Lee J;Kassiri Z
通讯作者：
Kassiri Z
影响因子：
16.2
作者：
Guyenet PG;Bayliss DA
通讯作者：
Bayliss DA
影响因子：
4.6
作者：
Hilfiger, Louis;Zhao, Qian;Charlet, Alexandre
通讯作者：
Charlet, Alexandre
影响因子：
7.3
作者：
Frantz, Marie-Celine;Pellissier, Lucie P.;Hibert, Marcel
通讯作者：
Hibert, Marcel
影响因子：
64.8
作者：
通讯作者：
--