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Investigating the Role of Vascular Endothelial Growth Factor in Hematopoietic Stem Cell Driven Perivascular Niche Remodeling
Author(s) -
Bubenheimer Rebecca K.,
Tamplin Owen J.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.843.25
Subject(s) - biology , haematopoiesis , stem cell , microbiology and biotechnology , progenitor cell , hematopoietic stem cell , mural cell , stem cell factor , vascular endothelial growth factor , zebrafish , bone marrow , endothelial stem cell , immunology , cancer research , vegf receptors , genetics , in vitro , gene
Hematopoiesis is the process that produces the entirety of mature blood cells. A balance between the quiescence and proliferation of hematopoietic stem cells (HSC) is essential to maintain the blood supply. During development, HSCs expand exponentially in an intermediate niche before migration to the adult bone marrow. In zebrafish, the intermediate niche is the caudal hematopoietic tissue (CHT), a vascular plexus in the tail of the embryo, and in mice it is the fetal liver. Previous work by Tamplin et al. 2015 showed that arrival of an HSC triggers endothelial cells (EC) in the CHT niche to remodel and form a pocket around the HSC. Our goal is to uncover the function of the EC pocket and the mechanism of its formation. One candidate for this signaling cascade is vascular endothelial growth factor C (VEGF‐C) and its receptors VEGFR2 and VEGFR3. Within all hematopoietic lineages, VEGF‐C is highly expressed in HSC. VEGFR2/3 are expressed on sinusoidal endothelial cells of the CHT and fetal liver niches. Previous studies have shown a decrease in hematopoietic progenitor numbers when VEGFR3 is knocked out in mouse embryos (Hamada, 2000). Our preliminary data in zebrafish embryos have agreed with these findings. We have seen a decrease in hematopoietic stem and progenitor cells in vivo marked by the transgenic reporter cd41:gfp and in whole mount in situ with c‐myb probe after knocking down VEGFR3 alone as well as in combination with VEGFR2. To further confirm this phenotype, we administered pan VEGFR inhibitor, Semaxinib, and saw a similar decrease in cd41:gfp+ progenitors. We plan to further investigate this phenotype with a variety of small molecule inhibitors, genetic mutants, and synthetic oligo “morpholino” knockdown. Once we establish the mechanism for VEGF signaling in the remodeling of the perivascular EC niche, we plan to investigate the downstream targets. Uncovering the signals that govern the interaction between HSCs and their perivascular niche is clinically applicable in improving the efficiency of HSC transplants. Support or Funding Information Department of Pharmacology, Lung and Vascular Biology Training Grant; NIH T32 HL027829 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .