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^hdf 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 VEGF₁₆₅. Hyaluronan was severely depleted in Vcan^hdf embryos, with corresponding upregulation of the hyaluronan-depolymerase TMEM2. Conversely, hyaluronan-deficient mouse embryos also had vasculogenic suppression but with increased versican proteolysis. VEGF₁₆₅ 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) 对胚胎中最早细胞谱系形成的贡献知之甚少。在这里，我们显示蛋白多糖多功能蛋白聚糖和糖胺聚糖透明质酸与原肠胚形成时出现的 Flk1 ⁺血内皮祖细胞相关。小鼠 versican 突变体Vcan ^hdf缺乏卵黄囊脉管系统，卵黄囊造血功能减弱。小鼠胚胎干细胞中CRISPR/Cas9 介导的Vcan失活减少了胚胎样体内的血管内皮和造血分化，从而产生较少的血集落，并且对 VEGF 的血管生成反应受损₁₆₅。透明质酸在Vcan ^{hdf中严重耗尽}胚胎，透明质酸解聚酶 TMEM2 相应上调。相反，缺乏透明质酸的小鼠胚胎也具有血管生成抑制，但具有增加的多功能蛋白水解。重要的血管生成因子VEGF ₁₆₅和印度刺猬利用 versican-透明质酸基质，特别是 versican 硫酸软骨素链进行结合。因此，Versican-透明质酸 ECM 是血管生成和原始造血的必要条件，为 Flk1 ⁺祖细胞在原肠胚形成时提供了富含血管生成因子的微生态系统。