Department of Biomedical Engineering (ND20), Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195, United States.
Human Genetics Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, United States.
Matrix Biol. 2021 Mar;97:40-57. doi: 10.1016/j.matbio.2021.01.002. Epub 2021 Jan 14.
Little is known about extracellular matrix (ECM) contributions to formation of the earliest cell lineages in the embryo. Here, we show that the proteoglycan versican and glycosaminoglycan hyaluronan are associated with emerging Flk1 hematoendothelial progenitors at gastrulation. The mouse versican mutant Vcan lacks yolk sac vasculature, with attenuated yolk sac hematopoiesis. CRISPR/Cas9-mediated Vcan inactivation in mouse embryonic stem cells reduced vascular endothelial and hematopoietic differentiation within embryoid bodies, which generated fewer blood colonies, and had an impaired angiogenic response to VEGF. Hyaluronan was severely depleted in Vcan embryos, with corresponding upregulation of the hyaluronan-depolymerase TMEM2. Conversely, hyaluronan-deficient mouse embryos also had vasculogenic suppression but with increased versican proteolysis. VEGF and Indian hedgehog, crucial vasculogenic factors, utilized the versican-hyaluronan matrix, specifically versican chondroitin sulfate chains, for binding. Versican-hyaluronan ECM is thus an obligate requirement for vasculogenesis and primitive hematopoiesis, providing a vasculogenic factor-enriching microniche for Flk1 progenitors from their origin at gastrulation.
关于细胞外基质 (ECM) 对胚胎中最早的细胞谱系形成的贡献，目前知之甚少。在这里，我们表明蛋白聚糖 versican 和糖胺聚糖透明质酸与原肠胚形成时出现的 Flk1 血内皮祖细胞有关。小鼠 versican 突变体 Vcan 缺乏卵黄囊血管，卵黄囊造血作用减弱。CRISPR/Cas9 介导的小鼠胚胎干细胞中 Vcan 的失活减少了类胚体中的血管内皮和造血分化，导致血液集落生成减少，对 VEGF 的血管生成反应受损。Vcan 胚胎中的透明质酸严重耗竭，相应地透明质酸解聚酶 TMEM2 上调。相反，缺乏透明质酸的小鼠胚胎也有血管生成抑制作用，但 versican 蛋白水解增加。血管生成的关键因子 VEGF 和印度刺猬hog，利用 versican-透明质酸基质，特别是 versican 软骨素硫酸盐链进行结合。因此，versican-透明质酸细胞外基质是血管生成和原始造血所必需的，为原肠胚形成时 Flk1 祖细胞提供了富含血管生成因子的小生境。
