Vascular endothelial growth factor-induced vascular permeability results in drastic and reversible hematopoietic stem cell mobilization

Abstract

Lifelong hematopoiesis as well as hematopoietic transplantation therapies is dependent on the ability of hematopoietic stem cells (HSCs) to effectively traffic across the bone marrow (BM) endothelium. Mounting evidence suggests that modulators of vascular permeability are potent regulators of HSC location. Here, we utilized a doxycycline-inducible mouse model to overexpress vascular endothelial growth factor A (VEGF-A) to alter vascular permeability. Remarkably, VEGF-induced permeability led to unprecedented HSC mobilization. HSC mobilization from the BM to the blood stream was rapid and reversible and required no additional drugs or manipulation. The mobilized HSCs were functional, as demonstrated by high levels of long-term multi-lineage reconstitution by VEGF-mobilized cells of irradiated recipients. Importantly, VEGF-induced permeability did not irrevocably destroy vascular BM niches, as transplantation experiments revealed improved long-term donor HSC engraftment in VEGF-overexpressing recipients. Collectively, these findings enhance our ability to regulate HSC trafficking to and from the BM and provide insight into improving the efficacy and safety of HSC mobilization and hematopoietic transplantation therapies.

Keywords: HSC engraftment; HSC mobilization; HSC trafficking; VEGF; bone marrow endothelium; hematopoietic stem cells; hematopoietic transplantation therapies; mouse model; transplantation; vascular endothelial growth factor; vascular niches; vascular permeability.