Single-Cell Transcriptomics Reveals Chemotaxis-Mediated Intraorgan Crosstalk During Cardiogenesis

作者：Haiqing Xiong, Yingjie Luo, Yanzhu Yue, Jiejie Zhang, Shanshan Ai, Xin Li, Xuelian Wang, Yun‐Long Zhang, Yusheng Wei, Hui‐Hua Li, Xinli Hu, Cheng Li, Aibin He · 发表于：Circulation Research · 年份：2019 · DOI：10.1161/circresaha.119.315243 · 被引用次数：75 · 研究领域：Congenital heart defects research、Cardiac Fibrosis and Remodeling、Cardiomyopathy and Myosin Studies

RATIONALE: We hypothesized that the differentiation processes of cardiac progenitor cell (CP) from first and second heart fields (FHF and SHF) may undergo the unique instructive gene regulatory networks or signaling pathways, and the precise SHF progression is contingent on the FHF signaling developmental cues. OBJECTIVE: We investigated how the intraorgan communications control sequential building of discrete anatomic regions of the heart at single-cell resolution. METHODS AND RESULTS: By single-cell transcriptomic analysis of Nkx2-5 (NK2 homeobox 5) and Isl1 (ISL LIM homeobox 1) lineages at embryonic day 7.75, embryonic day 8.25, embryonic day 8.75, and embryonic day 9.25, we present a panoramic view of distinct CP differentiation hierarchies. Computational identifications of FHF- and SHF-CP descendants revealed that SHF differentiation toward cardiomyocytes underwent numerous step-like transitions, whereas earlier FHF progressed toward cardiomyocytes in a wave-like manner. Importantly, single-cell pairing analysis demonstrated that SHF-CPs were attracted to and expanded FHF-populated heart tube region through interlineage communications mediated by the chemotactic guidance (MIF [macrophage migration inhibitory factor]-CXCR2 [C-X-C motif chemokine receptor 2]). This finding was verified by pharmacological blockade of this chemotaxis in embryos manifesting limited SHF cell migration and contribution to the growth of the outflow tract and right ventricle but undetectable effe...