Fate restriction of multipotent cardiovascular progenitor populations

心力衰竭是西方世界导致死亡的主要原因之一。这在一定程度上可以归因于人类心脏在受伤后再生能力有限。与斑马鱼或火蜥蜴等其他物种不同，人类心脏中死亡的心肌细胞不能被新细胞取代。相反，疤痕会限制心脏功能。人类心血管祖细胞发生在胚胎发育过程中，可以在体外从人类胚胎干细胞分化而来，具有作为再生医学治疗细胞来源的巨大潜力。它们可以分化为所有心脏谱系的细胞，是其他物种心脏再生的已知驱动力。然而，控制这些细胞的自我更新和命运决定等基本过程的细胞机制在很大程度上仍然难以捉摸，阻碍了这一有希望的方法的成功临床应用。这一建议的假设是，在人类胚胎干细胞体外分化过程中出现的多潜能心血管祖细胞群体不是同质群体，而是由多个亚群组成。这些亚群的分化能力不同，受不同的转录网络控制，对外源信号信号的反应也不同。该项目的主要目标是制定识别、分离和扩增不同心血管前体亚群的策略。为了实现这一目标，先进的单细胞技术(转录学和表观基因组学)将与基于病毒的谱系追踪相结合。所产生的知识将被进一步利用来建立新的工具，在模拟体内情况的新型3D细胞培养系统中，在时间和空间上控制这些细胞的放大和分化。这一有针对性的方法将提供关于心血管祖细胞亚群作为再生治疗的新细胞来源的治疗潜力的初步结果。

Heart failure is one of the leading causes for mortality in the western world. Partially, this can be attributed to the limited regenerative potential of the human heart after injury. In contrast to other species, like the zebrafish or salamanders, dead cardiomyocytes in the human heart cannot be replaced by new cells. Instead, scarring occurs limiting cardiac function. Human cardiovascular progenitor cells, which occur during embryogenesis and can be differentiated in vitro from human embryonic stem cells, harbor great potential as a therapeutic cell source for regenerative medicine. They can differentiate into cells of all cardiac lineages and are known drivers for cardiac regeneration in other species. However, the cellular mechanisms governing fundamental processes like self-renewal and fate-decision of these cells are still largely elusive hampering successful clinical translation of this promising approach. The hypothesis of this proposal is that the multipotent cardiovascular progenitor populations which arise during in vitro differentiation of human embryonic stem cells are not homogeneous populations but consist of multiple subpopulations. These subpopulations differ in their differentiation capacities, are governed by distinct transcriptional networks and respond differently to exogenous signaling cues. The main objective of the project is to develop strategies for identifying, isolating and amplifying the different cardiovascular progenitor subpopulations. To achieve this, advanced single cell technologies (transcriptomics and epigenomics) will be combined with virus-based lineage tracing. The knowledge generated will be further exploited to establish new tools to temporally and spatially control amplification and differentiation of these cells in a novel 3D cell-culture system mimicking the in vivo situation. This targeted approach will provide first results on the therapeutic potential of cardiovascular progenitor subpopulations as a novel cell source for regenerative therapies.