Sharma Bikram, Ho Lena, Ford Gretchen Hazel, Chen Heidi I, Goldstone Andrew B, Woo Y Joseph, Quertermous Thomas, Reversade Bruno, Red-Horse Kristy
Department of Biology, Stanford University, Stanford, CA 94305, USA.
Human Genetics and Embryology Laboratory, Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore.
Dev Cell. 2017 Sep 25;42(6):655-666.e3. doi: 10.1016/j.devcel.2017.08.008. Epub 2017 Sep 7.
Organogenesis during embryonic development occurs through the differentiation of progenitor cells. This process is extraordinarily accurate, but the mechanisms ensuring high fidelity are poorly understood. Coronary vessels of the mouse heart derive from at least two progenitor pools, the sinus venosus and endocardium. We find that the ELABELA (ELA)-APJ signaling axis is only required for sinus venosus-derived progenitors. Because they do not depend on ELA-APJ, endocardial progenitors are able to expand and compensate for faulty sinus venosus development in Apj mutants, leading to normal adult heart function. An upregulation of endocardial SOX17 accompanied compensation in Apj mutants, which was also seen in Ccbe1 knockouts, indicating that the endocardium is activated in multiple cases where sinus venosus angiogenesis is stunted. Our data demonstrate that by diversifying their responsivity to growth cues, distinct coronary progenitor pools are able to compensate for each other during coronary development, thereby providing robustness to organ development.
胚胎发育过程中的器官发生通过祖细胞的分化来实现。这一过程极其精确，但确保高保真度的机制却鲜为人知。小鼠心脏的冠状血管至少来源于两个祖细胞库，即静脉窦和心内膜。我们发现，ELABELA（ELA）-APJ信号轴仅对源自静脉窦的祖细胞是必需的。由于心内膜祖细胞不依赖ELA-APJ，它们能够增殖并补偿Apj突变体中静脉窦发育的缺陷，从而使成年心脏功能正常。Apj突变体中的心内膜SOX17上调伴随着这种补偿作用，Ccbe1基因敲除小鼠中也观察到了这一现象，这表明在静脉窦血管生成受阻的多种情况下，心内膜都会被激活。我们的数据表明，通过使不同的冠状祖细胞库对生长信号的反应多样化，它们能够在冠状动脉发育过程中相互补偿，从而为器官发育提供稳健性。
