近日，来自美国格莱斯顿心血管疾病研究所的Deepak Srivastava和Casey A. Gifford研究组合作利用心脏发生的单细胞测序揭示了器官水平发育缺陷的基础。2019年8月1日出版的《自然》发表了这项成果。

研究人员利用单细胞RNA测序技术研究了在经历正常和不正常的心脏发生变得特异之前的早期心脏前体细胞，并揭示了特定的细胞亚群失调如何带来灾难性后果。一个基于网络的计算方法分析了单细胞测序结果，预测了谱系特异的转录因子，并将Hand2鉴定为流出道细胞而不是右心室细胞的特化因子，尽管在Hand2缺失小鼠中右心室无法形成。Hand2缺失胚胎的时序性单细胞转录组分析揭示流出道心肌细胞特化的失败，而右心室心肌细胞发生特化，但没有正确分化并迁移。Hand2的缺失同样导致了视黄酸通路的失调以及心脏前体细胞前-后轴成型的紊乱。因此，这项工作揭示了在不同心脏前体细胞在命运特化与分化中转录决定因子，并在单细胞分辨率水平揭露了心脏发育紊乱的机制，从而为研究先天性心脏缺陷提供了框架。

据介绍，器官发生涉及多种细胞类型的整合；细胞类型特异性基因网络的失调会导致出生缺陷，这影响到5%的胎儿出生。先天性心脏缺陷是最常见的畸形，这由不同亚群的心脏前体细胞紊乱所导致，但不同的前体细胞中转录的改变如何导致器官水平的缺陷却未知。
 

附：英文原文

Title: Single-cell analysis of cardiogenesis reveals basis for organ-level developmental defects

Author: T. Yvanka de Soysa, Sanjeev S. Ranade, Satoshi Okawa, Srikanth Ravichandran, Yu Huang, Hazel T. Salunga, Amelia Schricker, Antonio del Sol, Casey A. Gifford, Deepak Srivastava

Issue&Volume: Volume 572 Issue 7767

Abstract: Organogenesis involves integration of diverse cell types; dysregulation of cell-type-specific gene networks results in birth defects, which affect 5% of live births. Congenital heart defects are the most common malformations, and result from disruption of discrete subsets of cardiac progenitor cells, but the transcriptional changes in individual progenitors that lead to organ-level defects remain unknown. Here we used single-cell RNA sequencing to interrogate early cardiac progenitor cells as they become specified during normal and abnormal cardiogenesis, revealing how dysregulation of specific cellular subpopulations has catastrophic consequences. A network-based computational method for single-cell RNA-sequencing analysis that predicts lineage-specifying transcription factors identified Hand2 as a specifier of outflow tract cells but not right ventricular cells, despite the failure of right ventricular formation in Hand2-null mice. Temporal single-cell-transcriptome analysis of Hand2-null embryos revealed failure of outflow tract myocardium specification, whereas right ventricular myocardium was specified but failed to properly differentiate and migrate. Loss of Hand2 also led to dysregulation of retinoic acid signalling and disruption of anteriorposterior patterning of cardiac progenitors. This work reveals transcriptional determinants that specify fate and differentiation in individual cardiac progenitor cells, and exposes mechanisms of disrupted cardiac development at single-cell resolution, providing a framework for investigating congenital heart defects.

DOI: 10.1038/s41586-019-1414-x

Source: https://www.nature.com/articles/s41586-019-1414-x