Fate restriction of multipotent cardiovascular progenitor populations

心脏衰竭是西方世界的主要死亡原因之一。部分原因是人类心脏损伤后的再生能力有限。与斑马鱼或蝾螈等其他物种相比，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。人心血管祖细胞发生在胚胎发生过程中，可在体外从人胚胎干细胞中分化出来，具有作为再生医学治疗细胞来源的巨大潜力。它们可以分化成所有心脏谱系的细胞，并且是其他物种心脏再生的已知驱动因素。然而，控制这些细胞自我更新和命运决定等基本过程的细胞机制仍然在很大程度上难以捉摸，阻碍了这种有前途的方法的成功临床转化。该假说认为，在人胚胎干细胞体外分化过程中产生的多能性心血管祖细胞群体不是同质群体，而是由多个亚群体组成的。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祖细胞亚群的策略。为了实现这一目标，先进的单细胞技术（转录组学和表观基因组学）将与基于病毒的谱系追踪相结合。所产生的知识将进一步被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扩增和分化。这种有针对性的方法将为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提供初步结果。

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.