Coronary blood vessels from distinct origins converge to equivalent states during mouse and human development.
Coronary blood vessels from distinct origins converge to equivalent states during mouse and human development.
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在小鼠和人类发育过程中，不同起源的冠状血管会聚到相同的状态。
DOI：
10.7554/elife.70246
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发表时间：
2021-12-15
期刊：
影响因子：
7.7
通讯作者：
Red-Horse K
中科院分区：
文献类型：
--
作者：
Phansalkar R;Krieger J;Zhao M;Kolluru SS;Jones RC;Quake SR;Weissman I;Bernstein D;Winn VD;D'Amato G;Red-Horse K
大多数细胞在发育过程中的命运轨迹遵循发散的、树状的分枝模式，但当不同的祖细胞贡献给相同的细胞类型时，可能会发生相反的情况。在这种趋同分化过程中，细胞是否在转录上“记住”它们的起源，或者这是否会影响细胞的行为，目前尚不清楚。大多数心脏冠脉起源于两种不同的前体来源--心内膜(Endo)和静脉窦(SV)，但是否保留了与起源相关的转录或功能差异尚不清楚。我们通过在胚胎和成年小鼠心脏中结合谱系追踪和单细胞RNA测序(ScRNAseq)来解决这个问题。冠状动脉发育开始后不久，毛细血管内皮细胞(ECs)转录分离成两种状态，保留祖细胞特异性基因表达。在发育后期，当冠状动脉血管系统建立良好但仍在重塑时，毛细血管内皮细胞再次分离为两个群体，但转录差异主要与组织定位有关，而不是血统。具体地说，心脏隔膜中的内皮细胞表达的基因表明局部缺氧增加和血流量减少。成体毛细血管内皮细胞在谱系和位置上都更为均匀。一致认为，在成人心脏中，SV和Endo来源的内皮细胞对损伤的反应相似。最后，发育中的人类冠状动脉的scRNAseq表明，人类的心脏遵循类似的原理。因此，在发育过程中，冠状动脉内皮细胞的转录异质性首先受到谱系的影响，然后受位置的影响，直到体内平衡的成人心脏中的异质性下降。这些结果突出了内皮细胞在发育过程中的可塑性，以及小鼠作为人类冠状动脉发育模型的有效性。
Most cell fate trajectories during development follow a diverging, tree-like branching pattern, but the opposite can occur when distinct progenitors contribute to the same cell type. During this convergent differentiation, it is unknown if cells ‘remember’ their origins transcriptionally or whether this influences cell behavior. Most coronary blood vessels of the heart develop from two different progenitor sources—the endocardium (Endo) and sinus venosus (SV)—but whether transcriptional or functional differences related to origin are retained is unknown. We addressed this by combining lineage tracing with single-cell RNA sequencing (scRNAseq) in embryonic and adult mouse hearts. Shortly after coronary development begins, capillary endothelial cells (ECs) transcriptionally segregated into two states that retained progenitor-specific gene expression. Later in development, when the coronary vasculature is well established but still remodeling, capillary ECs again segregated into two populations, but transcriptional differences were primarily related to tissue localization rather than lineage. Specifically, ECs in the heart septum expressed genes indicative of increased local hypoxia and decreased blood flow. Adult capillary ECs were more homogeneous with respect to both lineage and location. In agreement, SV- and Endo-derived ECs in adult hearts displayed similar responses to injury. Finally, scRNAseq of developing human coronary vessels indicated that the human heart followed similar principles. Thus, over the course of development, transcriptional heterogeneity in coronary ECs is first influenced by lineage, then by location, until heterogeneity declines in the homeostatic adult heart. These results highlight the plasticity of ECs during development, and the validity of the mouse as a model for human coronary development.