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 Vcanhdf 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 in embryoid bodies, which generated fewer blood colonies, and had an impaired angiogenic response to VEGF165. HA was severely depleted in Vcanhdf embryos, with corresponding increase in the HA-depolymerase TMEM2. Conversely, HA-deficient mouse embryos also had vasculogenic suppression but with increased versican proteolysis. VEGF165 and Indian hedgehog, crucial vasculogenic factors, utilized the versican-HA matrix, specifically versican chondroitin sulfate chains, for binding. Versican-HA ECM is an obligate requirement for vasculogenesis and primitive hematopoiesis, providing a vasculogenic factor-enriching microniche for Flk1+ progenitors from their origin at gastrulation.

中文翻译：

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versican-透明质酸复合物为Flk1 +血内皮祖细胞提供了重要的细胞外基质位

关于细胞外基质（ECM）对胚胎中最早的细胞谱系形成的贡献知之甚少。在这里，我们显示蛋白多糖versican和糖胺聚糖透明质酸与新出现的Flk1 +血内皮祖细胞相关。小鼠versican突变体Vcanhdf缺乏卵黄囊血管系统，卵黄囊造血功能减弱。小鼠胚胎干细胞中CRISPR / Cas9介导的Vcan失活减少了胚状体中的血管内皮和造血分化，从而减少了血菌落，并且对VEGF165的血管生成反应受损。HA在Vcanhdf胚胎中严重耗竭，HA解聚酶TMEM2相应增加。相反，HA缺陷型小鼠胚胎也具有血管生成抑制作用，但其versican蛋白水解作用增强。至关重要的血管生成因子VEGF165和印度刺猬利用versican-HA基质（特别是versican软骨素硫酸盐链）进行结合。Versican-HA ECM是血管生成和原始造血的必不可少的条件，它为Flk1 +祖细胞的起源提供了丰富的血管生成因子的微生态位。