Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2 mediated regeneration of sinusoidal endothelial cells

By A. Hooper, J. Butler, D. Nolan, A. Kranz, K. Iida, Mariko Kobayashi, H. Kopp, K. Shido, I. Petit, Kilangsungla Yanger and 9 more. Cell Stem Cell, 2009

639 citations recorded by the source corpus.

SUMMARY The phenotypic attributes and molecular determinants for the regeneration of bone marrow (BM) sinusoidal endothelial cells (SECs) and their contribution to hematopoiesis are unknown. We show that after myelosuppression VEGFR2 activation promotes reassembly of regressed SECs, reconstituting hematopoietic stem and progenitor cells (HSPCs). VEGFR2 and VEGFR3 expression are restricted to BM vasculature, demarcating a continuous network of VEGFR2+VEGFR3+Sca1− SECs and VEGFR2+VEGFR3−Sca1+ arterioles. While chemotherapy (5FU) and sublethal irradiation (650 rad) induce minor SEC regression, lethal irradiation (950 rad) induces severe regression of SECs requiring BM transplantation (BMT) for regeneration. Conditional deletion of VEGFR2 in adult mice blocks regeneration of SECs in sublethally irradiated animals, preventing hematopoietic reconstitution. Inhibition of VEGFR2 signaling in lethally irradiated wild type mice rescued with BMT severely impairs SEC reconstruction, preventing engraftment and reconstitution of HSPCs. Therefore, activation of VEGFR2 is critical for regeneration of VEGFR3+Sca1− SECs that are essential for engraftment and restoration of HSPCs and hematopoiesis.

Subfields: Genetics, Hematology

View Paper: https://www.semanticscholar.org/paper/fb1af5a29d50472cc4ef21ae43a0f63c671f887d

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Aviv Bergman
2. V. Mittal
3. D. Lyden
4. P. Frenette
5. Robert D. Leclerc

In Hematology

1. Sandra Pinho
2. D. Lyden
3. P. Frenette

Citations in the corpus

• Arteriolar niches maintain haematopoietic stem cell quiescence (2013, positive): “…the sinusoidal network, 3D visualisation of the BM vasculature highlighted the presence of small calibre (10–20µm) Sca-1 hi VEGFR2 + VEGFR3 − arterioles 24 , which were found predominantly in close proximity to the bone 25 and comprised a much smaller volumetric fraction 1.2 ± 0.1% of the BM (Fig.”
• Inductive angiocrine signals from sinusoidal endothelium are required for liver regeneration (2010, positive): “As the VEGF family plays a critical role in the regeneration of the BM SECs 6 , we hypothesized that VEGF-receptors 20 - 22 , including VEGFR2 or VEGFR3 also modulate LSEC function.”
• The lymphatic vasculature in disease (2011, background): “However, the safety of a treatment targeting VEGFR-2 and VEGFR-3 needs to be carefully addressed as, for example, hematopoietic reconstitution after irradiation for bone marrow depletion may require VEGFR-2 and VEGFR-3 expression in the bone marrow sinusoidal endotheliu”
• Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells (2010, methodology): “We have previously shown that SECs is essential for reconstitution of hematopoiesis after mye- loablation (Hooper et al., 2009).”