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促红细胞生成素通过提高Sca-1+干细胞的功能参与小鼠心肌梗死的修复

左琳¹, 李端端¹, 马秀霞¹, 石山慧¹, 吕定超², 申晶¹, 张炜芳³, 高尔和⁴, 曹济民^1,*

¹山西医科大学基础医学院生理学系，细胞生理学教育部重点实验室，太原 030001；²山西省长治市人民医院心内科，长治 046000；³山西医科大学机能实验中心，太原 030001；⁴天普大学医学院转化医学中心，费城，宾夕法尼亚州 19140，美国

摘要

心肌梗死(myocardial infarction, MI)是目前全球主要的死亡病因之一。随着临床治疗水平的提高，MI急性期的死亡率已显著下降，但其对心肌重构及心功能的长远影响仍无法有效防治。促红细胞生成素(erythropoietin, EPO)是一种糖蛋白细胞因子，具有促进造血、抗凋亡和促血管生成的作用。研究表明EPO在心脏缺血损伤、心力衰竭等心血管疾病中发挥心肌保护作用，机制与促进心脏祖细胞活化有关。本研究旨在探讨EPO是否可通过增强Sca-1+干细胞的活性促进MI的修复。通过直接注射法将达贝泊汀-α (darbepoetin alpha，一种长效EPO类似物，EPOanlg)注射到成年小鼠MI的交界区，观测MI面积、心脏重构及功能、心肌细胞凋亡及微血管密度变化。用磁性分选技术从新生和成年小鼠心脏中分离Lin− Sca-1+干细胞，分别用于克隆形成能力及EPO效应的测定。结果显示，和单纯的MI组相比，在体应用EPOanlg可显著降低MI面积、心肌细胞凋亡率，减轻左室腔的扩张，同时提高心功能、增加冠状动脉微血管的数量。在离体实验中，EPO可促进Lin− Sca-1+干细胞增殖和迁移，增强克隆形成能力，这一效应可能是通过EPO受体进一步活化下游的STAT-5/p38 MAPK信号通路实现的。以上结果提示，EPO可能通过促进Sca-1+干细胞活化来参与MI的修复过程。

关键词： 心肌梗死; 促红细胞生成素; 干细胞; 小鼠; 细胞迁移

Erythropoietin promotes myocardial infarction repair in mice by improving the function of Sca-1+ stem cells

ZUO Lin¹, LI Duan-Duan¹, MA Xiu-Xia¹, SHI Shan-Hui¹, LYU Ding-Chao², SHEN Jing¹, ZHANG Wei-Fang³, GAO Er-He⁴, CAO Ji-Min^1,*

¹Key Laboratory of Cellular Physiology, Ministry of Education, and the Department of Physiology, School of Basic Sciences, Shanxi Medical University, Taiyuan 030001, China；²Department of Cardiology, the People’s Hospital of Changzhi City, Changzhi 046000, China；³Center for Functional Experiments, Shanxi Medical University, Taiyuan 030001, China；⁴Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA

Abstract

Myocardial infarction (MI) is one of the leading causes of death in the world. With the improvement of clinical therapy, the mortality of acute MI has been significantly reduced. However, as for the long-term impact of MI on cardiac remodeling and cardiac function, there is no effective prevention and treatment measures. Erythropoietin (EPO), a glycoprotein cytokine essential to hematopoiesis, has anti-apoptotic and pro-angiogenetic effects. Studies have shown that EPO plays a protective role in cardiomyocytes in cardiovascular diseases, such as cardiac ischemia injury and heart failure. EPO has been demonstrated to protect ischemic myocardium and improve MI repair by promoting the activation of cardiac progenitor cells (CPCs). This study aimed to investigate whether EPO can promote MI repair by enhancing the activity of stem cell antigen 1 positive stem cells (Sca-1+ SCs). Darbepoetin alpha (a long-acting EPO analog, EPOanlg) was injected into the border zone of MI in adult mice. Infarct size, cardiac remodeling and performance, cardiomyocyte apoptosis and microvessel density were measured. Lin− Sca-1+ SCs were isolated from neonatal and adult mouse hearts by magnetic sorting technology, and were used to identify the colony forming ability and the effect of EPO, respectively. The results showed that, compared to MI alone, EPOanlg reduced the infarct percentage, cardiomyocyte apoptosis ratio and left ventricular (LV) chamber dilatation, improved cardiac performance, and increased the numbers of coronary microvessels in vivo. In vitro, EPO increased the proliferation, migration and clone formation of Lin− Sca-1+ SCs likely via the EPO receptor and downstream STAT-5/p38 MAPK signaling pathways. These results suggest that EPO participates in the repair process of MI by activating Sca-1+ SCs.

Key words: Myocardial infarction; erythropoietin; stem cells; mice; cell migration

收稿日期：　　录用日期：

通讯作者：曹济民　　E-mail:

DOI: 10.13294/j.aps.2023.0013

引用本文：

左琳, 李端端, 马秀霞, 石山慧, 吕定超, 申晶, 张炜芳, 高尔和, 曹济民. 促红细胞生成素通过提高Sca-1+干细胞的功能参与小鼠心肌梗死的修复[J]. 生理学报 2023; 75 (1): 36-48.

ZUO Lin, LI Duan-Duan, MA Xiu-Xia, SHI Shan-Hui, LYU Ding-Chao, SHEN Jing, ZHANG Wei-Fang, GAO Er-He, CAO Ji-Min. Erythropoietin promotes myocardial infarction repair in mice by improving the function of Sca-1+ stem cells. Acta Physiol Sin 2023; 75 (1): 36-48