Journal
MATRIX BIOLOGY
Volume 97, Issue -, Pages 40-57Publisher
ELSEVIER
DOI: 10.1016/j.matbio.2021.01.002
Keywords
Proteoglycan; Vasculogenesis; Angiogenesis; Endothelium; Hematopoiesis CRISPR-Cas9
Categories
Funding
- NIH-NHLBI Program of Excellence in Glycosciences award [HL107147]
- Allen Distinguished Investigator Program
- American Heart Association [17DIA33820024]
- NIH [RF1 AG057579]
- David and Lindsay Morgenthaler Postdoctoral Fellowship
- Mark Lauer Pediatric Research grant
- NIH SIG grant [1S10RR026820-01]
- Paul G. Allen Frontiers Group
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The study reveals that versican and hyaluronan are associated with the formation of early cell lineages in the embryo, with the versican-hyaluronan ECM playing a crucial role in vasculogenesis and primitive hematopoiesis. Inactivation of versican can lead to reduced vascular endothelial and hematopoietic differentiation, while hyaluronan-deficient mouse embryos also show vasculogenic suppression.
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 VEGF(165). 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. VEGF(165) 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. (C) 2021 Elsevier B.V. All rights reserved.
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