Generation of Cardiomyocytes From Vascular Adventitia-Resident Stem Cells
Generation of Cardiomyocytes From Vascular Adventitia-Resident Stem Cells
复制标题
DOI：
10.1161/circresaha.117.312526
复制
发表时间：
2018-08-31
影响因子：
20.1
通讯作者：
Erguen, Sueleyman
中科院分区：
文献类型：
--
作者：
Mekala, Subba Rao;Woersdoerfer, Philipp;Erguen, Sueleyman
理由：失去的心肌细胞的再生是导致心力衰竭的一个根本的未解决的问题。尽管从过去几十年的深入研究中发展出了几种策略，但心脏组织的内源性再生仍然有限，并且需要克服这一巨大挑战，才能成为心肌梗死的成功治疗选择。目的：心脏再生的基本前提之一是内源性心肌细胞祖细胞及其生态位的鉴定，这些细胞可用于新的治疗方法。在这种情况下，我们假设血管壁可能是心脏祖细胞的来源，血管壁被证明含有不同类型的干细胞和祖细胞。方法和结果：我们描述了在没有任何遗传操作的情况下产生自发跳动的小鼠主动脉壁源性心肌细胞。利用WT（野生型）、MHC（-肌球蛋白重链）和Flk1（胎儿肝激酶1）报告小鼠的主动脉壁源性细胞（AoCs）和GFP（绿色荧光蛋白）小鼠的Flk1(+) AoCs的磁珠相关细胞分选，我们确定Flk1(+)CD（分化簇）34(+)Sca-1（干细胞抗原-1）- cd44 (-) AoCs是产生主动脉壁源性心肌细胞的群体。这种AoC亚群也传递内皮细胞和巨噬细胞，在主动脉壁来源的心肌细胞中有特定的积聚。在体内，通过将荧光标记的aoc植入鸡胚心脏，研究了其心肌细胞分化能力。这些细胞获得心肌细胞样表型，如SRA（-肌动蛋白）表达所示。此外，小鼠心肌梗死后，冠状动脉内皮Flk1（+）和CD34（+）细胞增殖，迁移到心肌中，并表达胰岛素基因增强蛋白-1(is -1(+))，表明心血管祖细胞潜能。结论：我们的数据表明Flk1(+)CD34（+）血管外膜干细胞，包括冠状动脉外膜干细胞，是一种新的内源性心肌细胞来源。这一过程主要由内皮细胞和巨噬细胞支持。总之，冠状动脉外膜心脏干及其支持细胞的治疗性操作可能为促进心肌梗死后心脏再生和修复以及预防心力衰竭开辟新的途径。
Rationale: Regeneration of lost cardiomyocytes is a fundamental unresolved problem leading to heart failure. Despite several strategies developed from intensive studies performed in the past decades, endogenous regeneration of heart tissue is still limited and presents a big challenge that needs to be overcome to serve as a successful therapeutic option for myocardial infarction.Objective: One of the essential prerequisites for cardiac regeneration is the identification of endogenous cardiomyocyte progenitors and their niche that can be targeted by new therapeutic approaches. In this context, we hypothesized that the vascular wall, which was shown to harbor different types of stem and progenitor cells, might serve as a source for cardiac progenitors.Methods and Results: We describe generation of spontaneously beating mouse aortic wall-derived cardiomyocytes without any genetic manipulation. Using aortic wall-derived cells (AoCs) of WT (wild type), MHC (-myosin heavy chain), and Flk1 (fetal liver kinase 1)-reporter mice and magnetic bead-associated cell sorting sorting of Flk1(+) AoCs from GFP (green fluorescent protein) mice, we identified Flk1(+)CD (cluster of differentiation) 34(+)Sca-1 (stem cell antigen-1)-CD44(-) AoCs as the population that gives rise to aortic wall-derived cardiomyocytes. This AoC subpopulation delivered also endothelial cells and macrophages with a particular accumulation within the aortic wall-derived cardiomyocyte containing colonies. In vivo, cardiomyocyte differentiation capacity was studied by implantation of fluorescently labeled AoCs into chick embryonic heart. These cells acquired cardiomyocyte-like phenotype as shown by SRA (-sarcomeric actinin) expression. Furthermore, coronary adventitial Flk1(+) and CD34(+) cells proliferated, migrated into the myocardium after mouse myocardial infarction, and expressed Isl-1(+) (insulin gene enhancer protein-1) indicative of cardiovascular progenitor potential.Conclusions: Our data suggest Flk1(+)CD34(+) vascular adventitia-resident stem cells, including those of coronary adventitia, as a novel endogenous source for generating cardiomyocytes. This process is essentially supported by endothelial cells and macrophages. In summary, the therapeutic manipulation of coronary adventitia-resident cardiac stem and their supportive cells may open new avenues for promoting cardiac regeneration and repair after myocardial infarction and for preventing heart failure.