Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm 171 77, Sweden; Department of Medicine-Cardiology, Karolinska Institutet, Stockholm 141 86, Sweden.
Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm 171 77, Sweden.
Dev Cell. 2019 Feb 25;48(4):475-490.e7. doi: 10.1016/j.devcel.2019.01.005. Epub 2019 Jan 31.
The morphogenetic process of mammalian cardiac development is complex and highly regulated spatiotemporally by multipotent cardiac stem/progenitor cells (CPCs). Mouse studies have been informative for understanding mammalian cardiogenesis; however, similar insights have been poorly established in humans. Here, we report comprehensive gene expression profiles of human cardiac derivatives from multipotent CPCs to intermediates and mature cardiac cells by population and single-cell RNA-seq using human embryonic stem cell-derived and embryonic/fetal heart-derived cardiac cells micro-dissected from specific heart compartments. Importantly, we discover a uniquely human subset of cono-ventricular region-specific CPCs, marked by LGR5. At 4 to 5 weeks of fetal age, the LGR5 population appears to emerge specifically in the proximal outflow tract of human embryonic hearts and thereafter promotes cardiac development and alignment through expansion of the ISL1TNNT2 intermediates. The current study contributes to a deeper understanding of human cardiogenesis, which may uncover the putative origins of certain human congenital cardiac malformations.
哺乳动物心脏发育的形态发生过程复杂且受到多能性心脏干细胞/祖细胞 (CPCs) 的时空高度调控。小鼠研究为理解哺乳动物心脏发生提供了信息；然而，在人类中，类似的见解尚未得到充分证实。在这里，我们通过群体和单细胞 RNA-seq 报告了多能性 CPC 向中间和成熟心脏细胞的人类心脏衍生物的全面基因表达谱，使用了从特定心脏隔室微分离的人类胚胎干细胞衍生和胚胎/胎儿心脏衍生的心脏细胞。重要的是，我们发现了一个独特的人类心尖-室间隔区域特异性 CPC 亚群，由 LGR5 标记。在胎儿年龄 4 至 5 周时，LGR5 群体似乎专门出现在人类胚胎心脏的近端流出道中，此后通过 ISL1TNNT2 中间产物的扩张促进心脏发育和对齐。本研究有助于更深入地了解人类心脏发生，这可能揭示某些人类先天性心脏畸形的潜在起源。
