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Uncoupling VEGFA functions in arteriogenesis and hematopoietic stem cell specification.

Amy Leung¹, Aldo Ciau-Uitz, Philip Pinheiro

¹MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford University, OX3 9DS Oxford, UK.

Developmental Cell

|January 16, 2013

Summary

Vascular Endothelial Growth Factor A (VEGFA) signaling specifically induces hematopoietic stem cell (HSC) development. Medium/long VEGFA isoforms are crucial for HSC specification, independent of blood vessel formation.

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Area of Science:

Developmental Biology
Hematopoiesis
Molecular Biology

Background:

Vascular Endothelial Growth Factor A (VEGFA) signaling is essential for both endothelial and hematopoietic stem cell (HSC) development.
Perturbations in VEGFA signaling often lead to blood defects alongside impaired vascular development, obscuring its direct role in HSC specification.
Understanding the precise role of VEGFA in HSC formation is critical for both basic science and potential in vitro applications.

Purpose of the Study:

To investigate whether VEGFA directly contributes to hematopoietic stem cell (HSC) specification, independent of vascular development.
To elucidate the specific roles of different VEGFA isoforms in the developmental processes leading to HSCs.

Main Methods:

Knockdown of the regulator ETO2 during embryogenesis to specifically reduce medium/long Vegfa isoforms.
Analysis of Notch1 expression and HSC specification in the dorsal aorta (DA).
Utilizing Vegfa hypomorphs and isoform-specific morphants to study the effects of different Vegfa isoforms.

Main Results:

Knockdown of ETO2 led to decreased expression of medium/long Vegfa isoforms, resulting in absent Notch1 expression and failed HSC specification in the DA.
These defects occurred independently of vessel formation and arterial specification.
Vegfa hypomorphs and medium/long isoform morphants recapitulated the HSC specification failure, while the short VEGFA isoform was sufficient for dorsal aorta development.

Conclusions:

VEGFA signaling plays a direct and sequential role in HSC specification.
Medium/long VEGFA isoforms are specifically required for HSC specification, distinct from their role in vascular development.
VEGFA signaling sequentially induces endothelial, arterial, and HSC programs within the dorsal aorta.