Zhang Fengzhi, Qiu Hui, Dong Xiaohui, Zhang Xiaoyan, Wang Chunlan, Li Xin, Zhang Xingwu, Na Jie, Zhou Jin, Wang Changyong
Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
School of Life Sciences, Tsinghua University, Beijing 100084, China.
Life Med. 2022 Jun 14;1(2):179-195. doi: 10.1093/lifemedi/lnac002. eCollection 2022 Oct.
Human induced pluripotent stem cell (hiPSC)-derived cardiac organoids can be used to model human heart development and cardiovascular disease, and provide therapeutic cells to repair the heart. We used single-cell transcriptome analysis to dissect the development of 3D mini-cardiac organoids (MCOs) consisting of hiPSC-derived cardiomyocytes, and endothelial and smooth muscle cells. We found that the 3D matrix-rich microenvironment significantly promoted the maturation of cardiomyocytes, and mixing endothelial and smooth muscle cells with cardiomyocytes led to the formation of cardiac fibroblast highly expressing . Modulation of DLK1 signaling affected immunomodulatory gene expression in 2D cultured cardiomyocytes. Transplantation of multilineage MCO into a rat model of myocardial infarction significantly improved cardiac function and reduced fibrosis in the infarcted area. Our single-cell analysis of MCO provided rich information about cell state and fate dynamics in the 3D multilineage microenvironment and brought new insight into the molecular mechanism that promotes cardiomyocyte maturation and heart repair.
人诱导多能干细胞（hiPSC）来源的心脏类器官可用于模拟人类心脏发育和心血管疾病，并提供治疗性细胞来修复心脏。我们使用单细胞转录组分析来剖析由hiPSC衍生的心肌细胞、内皮细胞和平滑肌细胞组成的3D微型心脏类器官（MCO）的发育过程。我们发现富含3D基质的微环境显著促进了心肌细胞的成熟，并且将内皮细胞和平滑肌细胞与心肌细胞混合导致高表达的心脏成纤维细胞的形成。DLK1信号的调节影响二维培养心肌细胞中的免疫调节基因表达。将多谱系MCO移植到心肌梗死大鼠模型中可显著改善心脏功能并减少梗死区域的纤维化。我们对MCO的单细胞分析提供了有关三维多谱系微环境中细胞状态和命运动态的丰富信息，并为促进心肌细胞成熟和心脏修复的分子机制带来了新的见解。
